Infrequent Changes Research Articles

Using Live Imaging and FUCCI Embryonic Stem Cells to Rank DevTox Risks: Adverse Growth Effects of PFOA Compared With DEP Are 26 Times Faster, 1,000 Times More Sensitive, and 13 Times Greater in Magnitude.

Fluorescent ubiquitination-based cell cycle indicator (FUCCI) embryonic stem cells (ESCs), which fluoresce green during the S-G2-M phases, generate an S-shaped curve for the accumulation of cells during normal stemness (NS) culture with leukemia-inhibitory factor (LIF). Since it was hypothesized that a culture of ESCs was heterogeneous in the cell cycle, it was expected that increased S-G2-M-phases of the cell cycle would make an S-shaped curve parallel to the accumulation curve. Unexpectedly, it was observed that the fraction of FUCCI ESCs in green decreases over time to a nadir at ∼24 h after previous feeding and then rapidly enters S-G2-M-phases after medium change. G1 delay by infrequent medium change is a mild stress, as it does not affect growth significantly when frequency is increased to 12 h. Perfluoro-octanoic acid (PFOA) and diethyl phthalate (DEP) were used as examples of members of the per- and polyfluoroalkyl substances (PFAS) and phthalate families of chemicals, respectively. Two adverse outcomes were used to compare dose- and time-dependent effects of PFOA and DEP. The first was cell accumulation assay by time-lapse confluence measurements, largely at Tfinal/T74 h. The second was by quantifying dominant toxicant stress shown by the suppression of mild stress that creates a green fed/unfed peak. In terms of speed, PFOA is 26 times faster than DEP for producing a time-dependent LOAEL dose at 100 uM (that is, 2 h for PFOA and 52 h for DEP). PFOA has 1000-fold more sensitive LOAEL doses than DEP for suppressing ESC accumulation (confluence) at day 3 and day 2. There were two means to compare the magnitude of the growth suppression of PFOA and DEP. For the suppression of the accumulation of cells measured by confluence at Tfinal/T74h, there was a 13-fold suppression at the highest dose of PFOA > the highest dose of DEP. For the suppression of entry into the cell cycle after the G1 phase by stress on day 1 and 2, there is 10-fold more suppression by PFOA than DEP. The data presented here suggest that FUCCI ESCs can assay the suppression of accumulated growth or predict the suppression of future growth by the suppression of fed/unfed green fluorescence peaks and that PFOA’s adverse effects are faster and larger and can occur at more sensitive lower doses than DEP.

The longitudinal trajectories of online engagement over a full program

Student engagement has a trajectory (a timeline) that unfolds over time and can be shaped by different factors including learners’ motivation, school conditions, and the nature of learning tasks. Such factors may result in either a stable, declining or fluctuating engagement trajectory. While research on online engagement is abundant, most authors have examined student engagement in a single course or two. Little research has been devoted to studying online longitudinal engagement, i.e., the evolution of student engagement over a full educational program. This learning analytics study examines the engagement states (sequences, successions, stability, and transitions) of 106 students in 1396 course enrollments over a full program. All data of students enrolled in the academic year 2014–2015, and their subsequent data in 2015–2016, 2016–2017, and 2017–2018 (15 courses) were collected. The engagement states were clustered using Hidden Markov Models (HMM) to uncover the hidden engagement trajectories which resulted in a mostly-engaged (33% of students), an intermediate (39.6%), and a troubled (27.4%) trajectory. The mostly-engaged trajectory was stable with infrequent changes, scored the highest, and was less likely to drop out. The troubled trajectory showed early disengagement, frequent dropouts and scored the lowest grades. The results of our study show how to identify early program disengagement (activities within the third decile) and when students may drop out (first year and early second year).

Frequency of longitudinal changes in TP53 mutation status from gene sequencing of serial tumor biopsies from a large cohort of cancer patients.

3124 Background: The p53 pathway is one of the most important in cancer biology, with mutation of the TP53 gene that encodes the p53 tumor suppressor protein observed in ≈50% of all cancers. We evaluated the frequency of changes in TP53 mutation status in a large cohort of serial tumor biopsies. Methods: From a database of >200,000 next-generation gene sequencing results we identified 16,592 samples arising from repeat biopsies from 7840 patients (pts), average 2.12 per pt, 1007 pts with ≥3, max 11; over an interval up to 234 months (mos), average 11.0 mos. TP53 mutations with known or unknown significance in successive biopsies and changes in assignment from TP53-Wild-Type (WT) to Mutant (Mut), or Mut to WT, were evaluated vs. cancer type and time between biopsies. Results: Table: N (%) of samples vs. change in TP53 status from previous biopsy vs. mos from initial biopsy in all samples (7840 initial + 8752 successive, 46% TP53-Mut) and the three most represented cancers: non-small cell lung cancer (NSCLC, 1189 initial + 1268 successive, 60% Mut), breast (947 initial + 993 successive, 55% Mut), multiple myeloma (MM, 578 initial + 981 successive, 18% Mut). Conclusions: Changes in TP53 status were rare (<10% of samples). Differences may occur in serial biopsy samples for pathophysiological reasons, e.g., a mutant clone becoming dominant and/or heterogeneity at different tumor biopsy sites, or analytical differences in biopsy tumor content or assay sensitivity between samples. In this analysis, WT-to-Mut changes were more frequent (5.9%) than Mut-to-WT changes (3.3%), suggesting a small selection pressure for TP53 alterations later in oncogenesis and indicating that these alterations are truncal. Mut-to-WT changes are not readily explained physiologically and may suggest these infrequent changes are mostly due to sampling or analytical variability, and genuine changes in TP53 mutation status are quite rare.[Table: see text]

Identification of Continuous-time Linear Time-varying Systems with Abrupt Changes in Parameters

Abstract In this paper, we propose an adaptive identification method for continuous-time systems with slowly time-varying parameters subject to infrequent abrupt changes using sampled data in the presence of measurement noise. The proposed estimator consists of two steps. First, the time-derivatives of the input and output signals are approximated through a combination of a Kalman filter and fixed-interval smoother. The parameters of the time-varying system are then estimated using the approximate time-derivatives by two Kalman filters running forward and backward in time to track the abrupt changes. The performance of the proposed estimator is verified through simulation studies where it is shown to perform better than an existing direct continuous-time estimator.

Difference in Medication Adherence Between Patients Prescribed a 30‐Day Versus 90‐Day Supply After Acute Myocardial Infarction

BackgroundEvidence‐based medication adherence rates after a myocardial infarction are low. We hypothesized that 90‐day prescriptions are underused and may lead to higher evidence‐based medication adherence compared with 30‐day fills.Methods and ResultsWe examined patients with myocardial infarction treated with percutaneous coronary intervention between 2011 and 2015 in the National Cardiovascular Data Registry. Linking to Symphony Health pharmacy data, we described the prevalence of patients filling 30‐day versus 90‐day prescriptions of statins, β‐blockers, angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and P2Y12 inhibitors after discharge. We compared 12‐month medication adherence rates by evidence‐based medication class and prescription days' supply and rates of medication switches and dosing changes. Among 353 259 patients with myocardial infarction treated with percutaneous coronary intervention, 90‐day evidence‐based medication fill rates were low: 13.0% (statins), 12.3% (β‐blockers), 14.6% (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers), and 9.7% (P2Y12 inhibitors). Patients filling 90‐day prescriptions were more likely older (median 69 versus 62 years) with a history of prior myocardial infarction (25.0% versus 17.9%) or percutaneous coronary intervention (30.3% versus 19.5%; P<0.01 for all) than patients filling 30‐day prescriptions. The 12‐month adherence rates were higher for patients who filled 90‐day versus 30‐day supplies: statins, 83.1% versus 75.3%; β‐blockers, 72.7% versus 62.9%; angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, 71.1% versus 60.9%; and P2Y12 inhibitors, 78.5% versus 66.6% (P<0.01 for all). Medication switches and dosing changes within 12 months were infrequent for patients filling 30‐day prescriptions—14.7% and 0.3% for 30‐day P2Y12 inhibitor fills versus 6.3% and 0.2% for 90‐day fills, respectively.ConclusionsPatients who filled 90‐day prescriptions had higher adherence and infrequent medication changes within 1 year after discharge. Ninety‐day prescription strategies should be encouraged to improve post–myocardial infarction medication adherence.

From workplace to home environment: spreading of mouse allergens by laboratory animal workers

PurposeLaboratory animal workers (LAW) working with laboratory mice are exposed to mouse allergens (MA). If MA are spread to home environments, this might increase the risk for allergies in LAW and their families. This study aimed to assess 1. whether spreading of MA from workplace to home environment takes place; 2. which factors increase spreading of MA.MethodsIn a cross-sectional study, dust samples were taken on the mattress and seating in homes of LAW (n = 105) and an unexposed comparison group (n = 13). From 89 LAW, additional dust samples were taken from their workplaces. Samples were analysed using Mus m1 ELISA kits [detection limit (DL) 0.2 ng mus m1/ml]. Sociodemographic data, personal history of allergies and cleaning habits, as well as work-related characteristics (LAW only) were assessed by questionnaire. Latent factors were assessed via factor analysis. Tobit models were fitted to analyse the latent factors’ contribution to MA spreading.ResultsMA concentration on the seating was significantly higher in home environments of LAW (median = 1.28 ng mus m1/m2) than in the comparison group (median < DL, p = 0.019). The highest workplace MA concentration was found on the floor of the scullery (median = 140,000.00 ng mus m1/m2), followed by hair-covering caps (median = 76.02 ng mus m1/m2). Cage and mouse facility cleaning tasks and infrequent changing of bed linen at home were statistically significantly associated with higher MA concentrations at home.ConclusionsSpreading of MA from LAW’s workplace to their home environment takes place, especially among LAWs involved in cleaning tasks.

Mismatch Negativity and Impaired Social Functioning in Long-Term and in First Episode Schizophrenia Spectrum Psychosis.

Mismatch negativity (MMN) is elicited by infrequent physical parameter sound changes. MMN to pitch-deviants (pMMN) and duration-deviants (dMMN) are severely reduced in long-term schizophrenia (Sz). Although symptom factors (positive, negative, cognitive) are inconsistently associated with MMN amplitude in Sz, several studies have shown smaller dMMN is associated with impaired social functioning in Sz. MMN is less reduced at the first psychotic episode in the schizophrenia spectrum (FESz). Meta-analyses demonstrate that pMMN is not reduced, while dMMN is moderately impaired. Correlations of pMMN and dMMN with symptom factors in FESz are also equivocal. Associations with social functioning have not been reported. FESz and matched controls (n = 40/group), and Sz and matched controls (n = 50/group) were assessed for baseline and current cognitive functioning, symptoms, and social functioning, and pMMN and dMMN were recorded. Sz showed reductions in pMMN (p = 0.001) and dMMN (p = 0.006) amplitude. By contrast, pMMN (p = 0.27) and dMMN (p = 0.84) were not reduced in FESz. However, FESz showed associations between both MMNs and negative symptoms and social functioning. More impaired MMNs in FESz were associated with increased negative symptoms and impaired social functioning, both current and in the year prior to the emergence of psychosis. These data suggest that the extent of pathological process occurring before first psychosis as reflected in compromised social behavior prior to first break and reduced interpersonal communication and increased alogia at first break is indexed by pMMN and dMMN, putative biomarkers of disease progression sensitive to functional impairment.

MARLA-SG: Multi-Agent Reinforcement Learning Algorithm for Efficient Demand Response in Smart Grid

The population is sharply growing in the last decade, resulting in non-potential power requests in dense urban areas, especially with the traditional power grid where the system is not compatible with the infrequent changes. Smart grids have shown strong potential to effectively mitigate and smooth power consumption curves to avoid shortages by adjusting and forecasting the cost function in real-time in response to consumption fluctuations to achieve the desired objectives. The main challenge for the smart grid designers is to reduce the cost and Peak to Average Ratio (PAR) while maintaining the desired satisfaction level. This article presents the development and evaluation of a Multi-Agent Reinforcement Learning Algorithm for efficient demand response in Smart Grid (MARLA-SG). Also, it shows a simple and flexible way of choosing state elements to reduce the possible number of states, regardless of the device type, range of operation, and maximum allowable delay. It also produces a simple way to represent the reward function regardless of the used cost function. SARSA (State-Action-Reward-State-Action) and Q-learning schemes are used and attained PAR reduction of 9.6%, 12.16%, and an average cost reduction of 10.2%, 7.8%, respectively.

Dermatosurgery Practice and Implications of COVID-19 Pandemic: Recommendations by IADVL SIG Dermatosurgery (IADVL Academy).

Dermatosurgery Practice and Implications of COVID-19 Pandemic: Recommendations by IADVL SIG Dermatosurgery (IADVL Academy).

Analyzing the Effects of Temporal Resolution and Classification Confidence for Modeling Land Cover Change with Long Short-Term Memory Networks

Land cover change (LCC) is typically characterized by infrequent changes over space and time. Data-driven methods such as deep learning (DL) approaches have proven effective in many domains for predictive and classification tasks. When applied to geospatial data, sequential DL methods such as long short-term memory (LSTM) have yielded promising results in remote sensing and GIScience studies. However, the characteristics of geospatial datasets selected for use with these methods have demonstrated important implications on method performance. The number of data layers available, the rate of LCC, and inherent errors resulting from classification procedures are expected to influence model performance. Yet, it is unknown how these can affect compatibility with the LSTM method. As such, the main objective of this study is to explore the capacity of LSTM to forecast patterns that have emerged from LCC dynamics given varying temporal resolutions, persistent land cover classes, and auxiliary data layers pertaining to classification confidence. Stacked LSTM modeling approaches are applied to 17-year MODIS land cover datasets focused on the province of British Columbia, Canada. This geospatial data is reclassified to four major land cover (LC) classes during pre-processing procedures. The evaluation considers the dataset at variable temporal resolutions to demonstrate the significance of geospatial data characteristics on LSTM method performance in several scenarios. Results indicate that LSTM can be utilized for forecasting LCC patterns when there are few limitations on temporal intervals of the datasets provided. Likewise, this study demonstrates improved performance measures when there are classes that do not change. Furthermore, providing classification confidence data as ancillary input also demonstrated improved results when the number of timesteps or temporal resolution is limited. This study contributes to future applications of DL and LSTM methods for forecasting LCC.

Discrepancy Between Internal and External Intracranial Pressure Transducers: Quantification of an Old Source of Error in EVDs?

Intracranial pressure monitoring remains the foundation for prevention of secondary injury after traumatic brain injury and is most commonly performed using an external ventricular drain or intraparenchymal pressure monitor. The Integra Flex ventricular catheter combines an external ventricular catheter with a pressure transducer embedded in the tip of the catheter to allow continuous pressure readings while simultaneously draining cerebrospinal fluid. Discrepancies between measurements from the continuously reported internal pressure transducer and intermittently assessed and externally transduced ventricular drain prompted an analysis and characterization of pressures transduced from the same ventricular source. More than 500 hours of high-resolution (125 Hz) continuous recordings were manually reviewed to identify 73 hours of simultaneous measurements (clamped external ventricular drain) from internal and external transducers in patients with traumatic brain injury. A significant positive bias was found in pressure readings obtained from external relative to internal measurements. The 2 methods of measurement generally correlated poorly with each other and variably. Although proportional bias was found with Bland-Altman analysis, coherence revealed rare shifts in the external transducer as a major source of discrepancy. Infrequent changes in the 0-level of the external transducer were found to be the primary source of discrepancy. Relative to the observed differences, no significant trend was observed over time between the 2 modalities. This study suggests that the internal pressure transducer may be a more reliable estimate of intracranial pressure relative to bedside external transducers due to the inherent behavioral requirement of leveling.

The dual CUSUM charts with auxiliary information for process mean

The CUSUM chart is usually designed based on a known shift size when monitoring the process mean. In practice, shift size is rarely known but it can be assumed to vary within an interval. With such a range of shift size, the dual CUSUM (DCUSUM) chart provides more sensitivity than the CUSUM chart. In this paper, auxiliary information based (AIB) DCUSUM and dual Crosier CUSUM (DCCUSUM) charts with and without fast initial response (FIR) features are proposed for efficiently monitoring the infrequent changes in the process mean, named the AIB-DCUSUM and AIB-DCCUSUM charts, respectively. Monte Carlo simulations are used to compute the run length characteristics of these control charts. The AIB-DCUSUM and AIB-DCCUSUM charts with and without FIR features are compared with the DCUSUM, DCCUSUM and AIB-CUSUM charts in terms of the integral relative average run length. It is found that the proposed charts show better performance when detecting mean shifts in different ranges. A simulated dataset is considered to illustrate the implementation of existing and proposed charts.

Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome

BackgroundEnhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined. MethodsWe employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features. FindingsAcute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels. InterpretationARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.

THE HISTORY AND DEVELOPMENT OF THE SAINT LUCIA CIVIL CODE

The Civil Code of St. Lucia was copied almost verbatim from the Québec Civil Code and promulgated in the island in 1879, with minor influences from the Civil Code of Louisiana. It has constantly marvelled both West Indians and visitors to the region alike, that of all the former British Caribbean territories which were subjected to the vicissitudes of the armed struggles in the region between the Metropolitan powers resulting infrequent changes is sovereignty from one power to the other, only St. Lucia, after seventy-six years of uninterrupted British rule since its last cession by the French, managed to introduce a Civil Code which in effect was in direct conflict in most respects with the laws obtaining in its parent country. This is an attempt to examine the forces which were constantly at work in order to achieve this end, and the resoluteness of their efforts.

A User-Centric CPU-GPU Governing Framework for 3-D Mobile Games

Graphics-intensive mobile games place different and varying levels of demand on the associated central processing units (CPUs) and graphics processing units (GPUs). In contrast to the workload variability that characterizes games, the current design of the energy governor employed by mobile systems appears to be outdated. In this paper, we review the energy-saving mechanism implemented in an Android system coupled with graphics-intensive gaming workloads from three perspectives: 1) user perception; 2) application status; and 3) the interplay between the CPU and GPU. We observe that there are information gaps in the current system, which may result in unnecessary energy wastage. To resolve the problem, we propose an online user-centric CPU-GPU governing framework. To bridge the identified information gaps, we classify rendered game frames into redundant/changing frames to satisfy user demand , categorize an application into GPU sensitive/insensitive phases to understand the application’s demand , and determine the frequency scaling intents of the CPU and GPU to capture processor demand . In response to the measured demand, we employ a required workload estimator, a unified policy selector, and a frequency-scaling intent communicator in the framework to save energy. The proposed framework was implemented on an LG Nexus 5X smartphone, and extensive experiments with real-world 3-D gaming applications were conducted. According to the experiment results, for an application which is low interactive and infrequent phase changing, the proposed framework can, respectively, reduce energy consumption by 25.3% and 39% compared with our previous work and Android governors while maintaining user experience.

SAT-146 Short-Term Optimization of Glucose Control Using Self-Monitored Blood Glucose and Standard Therapies

BACKGROUND Achieving diabetes control often takes months to years with intermittent clinic visits, infrequent changes in therapy and management by HbA1c levels. We conducted a study testing whether glucose control could be improved within 8 weeks by employing structured self-monitoring of blood glucose (SMBG), short-term follow-up with diabetes education and medication changes. METHODS 97 adults provided informed consent were screened and 78 completed the study. Participants had T1DM or T2DM, HbA1c ≥8%, and Cr <2.0 mg/dL. A CBC and sCr were done at the baseline visit, HbA1c at every visit. Patients were evaluated by a physician and CDE at each visit and treatment was adjusted to reach target blood glucose (90-120 mg/dl before meals, <180 mg/dl after meals) and to avoid hypoglycemia by one of the following methods: diabetes education, add or increase the dose of an oral anti-diabetic agent and add or change the dose of insulin according to standard treatment guidelines at baseline and weeks 2 and 4. Patients were provided with glucose meters and test strips, and were instructed to test 4x daily, complete a 7-point profile before visits 2, 4 and 8 and kept written glucose logs. . The mean HbA1c and mean glucose on the 7-point profile were compared using one-way repeated measure Analysis of Variance between baseline and subsequent visits RESULTS Of the 78 patients, 64.1% had T2DM, 50% were females and 72% were Caucasians. Mean age (±SD) was 51.3±11.1 years, the median (interquartile range) for diabetes duration was 9 (5-17) years and sCr was 0.85 (0.7-1.0) mg/dL. 53.9% had hypertension, 12.8% retinopathy, 17.9% neuropathy and 2.6% nephropathy. Anti-diabetes medications included metformin 39.7%, sulfonylureas 31.1%, thiazolidinediones 23.1%, insulin 58.9%, including 7.7% who used insulin pumps. The percentage of patients using insulin increased from 58.9% at baseline to 67.9% at week 8. The mean (±SD) HbA1C was 9.53% (1.71) at baseline, 9.10% (1.50) at week 2, 8.80% (1.37) at week 4 and 8.15% (1.19) at week 8, representing a decline of -0.39% from baseline to week 2 (CI -0.65 to -0.16, p<0.001); -0.33% (CI -0.56 to -0.09 p=0.002) from week 2 to week 4; -0.65% (CI -0.89 to -0.42 p<0.001) from week 4 to week 8 and -1.38% from baseline to week 8 (CI -1.62 to -0.14, p<0.001). The mean (±SD) glucose on the 7-point profile was 187.11 (52.60) mg/dL at week 2, 176.21 (48.96) mg/dL at week 4, 157.51 (5.73) mg/dL at week 8, it declining -26.02 mg/dL (CI -42.32 to 0.70, p=0.001) from week 2 to week 8. CONCLUSION An intensive glucose optimization program conducted in patients with poorly controlled diabetes was successful in reducing HbA1c over 8 weeks. Increased SMBG, diabetes education and conventional medication adjustments were the key drivers. This structured optimization method improves glucose control safely and rapidly, and may be useful in pre-operative patients and those with limited access to more advanced diabetes therapies.

New adaptive EWMA control charts for monitoring univariate and multivariate coefficient of variation

The coefficient of variation (CV), a measure of relative variability, is an important quality control issue worthy of consideration in some manufacturing and service-oriented companies when the process mean is not constant and/or the process variance is a function of the process mean. In this paper, we propose two adaptive EWMA (AEWMA) charts for monitoring the infrequent changes in the CV and multivariate CV (MCV) when sampling from univariate and multivariate normally distributed processes, named the AEWMA CV and AEWMA MCV charts, respectively. With extensive Monte Carlo simulations, the run length characteristics of the proposed control charts are computed. It is found that the AEWMA CV chart performs substantially and uniformly better than the existing optimal EWMA and CUSUM CV charts when detecting moderate-to-large shifts in the process CV. Moreover, the AEWMA MCV chart also performs substantially and uniformly better than the existing Shewhart MCV chart. The proposed control charts are implemented on real datasets to support the theory.

A new dual CUSUM mean chart

AbstractThe conventional cumulative sum (CUSUM) chart is usually designed based on a known shift size. In usual practice, shift size is often unknown and can be assumed to vary within an interval. With such a range of shift size, the dual CUSUM (DCUSUM) chart provides more sensitivity than the CUSUM chart. In this paper, we propose dual Crosier CUSUM (DCCUSUM) charts with and without fast initial response features to efficiently monitor the infrequent changes in the mean of a normally distributed process. Monte Carlo simulations are used to compute the run length characteristics of one‐sided and two‐sided DCCUSUM charts. These run length characteristics are compared with those of the CUSUM, Crosier CUSUM, Shewhart‐CUSUM, and DCUSUM charts in terms of the integral relative average run length. It turns out that the proposed chart shows better performance when detecting a range of mean shift sizes. A real dataset is considered to illustrate the implementation of existing and proposed charts.

An adaptive multivariate EWMA chart

Abstract The adaptive multivariate EWMA (AMEWMA) and adaptive multivariate CUSUM (AMCUSUM) charts are recently proposed as they provide an overall good detection over a range of mean shift sizes than their non-adaptive conventional counterparts. In this paper, we propose an adaptive MEWMA (AMEWMA) chart for monitoring the infrequent changes in the mean of a multivariate normally distributed process. The idea is to consider an unbiased estimator of the mean shift using an MEWMA statistic, and then use it to adaptively update the smoothing constant of the MEWMA chart. By using Monte Carlo simulations, the run length characteristics of the AMEWMA chart are computed. The AMEWMA chart is comprehensively compared with the existing AMEWMA and AMCUSUM charts in terms of the average run length when detecting mean shifts in different ranges. It is found that the proposed chart is able to perform uniformly and substantially better than the existing charts. Both real and simulated datasets are considered to support the theory.

Abstract 1185: Synergistic drug combinations promote expansion of partially-resistant subpopulations in computational modeling of cancer heterogeneity and graded plasticity

Abstract Introduction: Synergistic drug combinations are widely sought as anti-cancer strategies because they yield higher therapeutic efficacy than additive or antagonistic combinations, enabling reduced doses. The effect of synergistic drugs (versus non-synergistic drugs) on the process of drug resistance evolution is not well understood, particularly for heterogeneous cell populations and for gradual phenotype transitions toward resistance. In this work, we use computational modeling of cancer cell numbers to interrogate the dynamics of resistance evolution during treatment with two-drug combinations. Methods: We developed computational models of cancer evolution under two-drug combination therapy, to study the development of drug resistance in cancers with varying heterogeneity or graded plasticity of resistance. A large population of cells was simulated to undergo infrequent but stochastic phenotype change over time, subject to a pharmacological dosing model of combination effects. Results: When synergistic and non-synergistic combinations were administered at equally effective doses in silico, drug resistance evolved more rapidly under the synergistic drugs. When we modeled graded plasticity by simulating multiple levels of drug resistance, results were similar except with additional bottlenecks before fully resistant cells could emerge. Meanwhile, as heterogeneity increased, synergism increased the speed of forming resistant subclones with higher fitness. Because synergistic treatments by nature exploit the simultaneous action of both drugs for their efficacy, the development of partial or single-drug resistance caused a disproportionate escape from drug effects and faster clonal expansion under synergistic therapy, compared with additive or non-synergistic therapies. Our simulations consistently showed that pairs of drugs with less synergism were able to prolong the time until double-resistance arose, provided the comparison combinations were dosed for equal initial efficacy. Conclusion: We identify dosing criteria whereby synergistic pairs of drugs actually have worse performance than additive or non-synergistic pairs, for delaying the onset of double-drug resistance. Dosing criteria are also shown for graded resistance and variable levels of population heterogeneity. Future work must examine non-heritable contributions to resistance, such as micro-environmental effects. Our theoretical work shows the need for further study of the divergence between short-term and long-term drug efficacy in the presence of clonal selection, and suggests increased attention to non-synergistic drug combinations as therapeutic candidates. Citation Format: Elysia C. Saputra, Lu Huang, Lisa Tucker-Kellogg. Synergistic drug combinations promote expansion of partially-resistant subpopulations in computational modeling of cancer heterogeneity and graded plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1185.