Distribution-based Analysis Research Articles

An empirical investigation of the distribution of travellers’ willingness-to-pay: A comparison between a parametric and nonparametric approach

Understanding the distribution of the willingness-to-pay (WTP) to reduce travel time or other unpleasant travel attributes experienced by travellers is crucial to making well-informed choices about infrastructure investments and the pricing of services. Given multimodality, heavy tails, and the impact of averaging errors in the classical parametric distribution-based analysis of WTP, this study compares WTP distributions across six distinct datasets using a range of model specifications, including multinomial logit (MNL), mixed logit (MMNL) and nonparametric logit mixed logit (LML). The models are estimated directly in willingness-to-pay space, highlighting that WTP is not uniformly distributed with a high likelihood of having a multi-modal distribution across the population. The findings confirm the intuition on the presence of negative WTP for some undesirable travel attributes. This study raises awareness among transport researchers, modellers, and authorities about using the correct WTP distributions in practice. It adds some empirical evidence regarding the true underlying WTP distribution of various travel attributes to the transport literature.

Establishing Meaningful Change Thresholds in Patient-Reported Outcomes Among Patients With Anaplastic Lymphoma Kinase-Positive Non–Small Cell Lung Cancer in ALTA-1L Trial

ObjectivesAn earlier study from the ALTA-1L trial of patients with anaplastic lymphoma kinase-positive non–small cell lung cancer demonstrated that brigatinib produces superior health-related quality of life (QoL) outcomes over crizotinib. This study aimed to derive meaningful change thresholds (MCTs) for European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 to refine the earlier results. MethodsPatients from the ALTA-1L trial were administered the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Responses were analyzed using anchor-based analysis, graphical analysis, distribution-based analysis, longitudinal responder analysis, and time to deterioration. ResultsThe patient-reported outcome population comprised 262 patients who completed the EORTC QLQ-C30 at baseline and at least 1 follow-up timepoint. Both anchors (QLQ-C30 items for overall health and QoL) had correlations >0.40 or < −0.40 with all functioning domains, fatigue, pain, appetite loss, and all dyspnea scores. Within-group analysis for most scales found the derived MCT was consistent with a cutoff of 10 points for classifying individual-patient change, except for 3-item dyspnea. The probability of improvement/remaining stable was significantly greater in the brigatinib group over crizotinib for the EORTC QLQ-C30 emotional functioning, appetite loss, and constipation domains. ConclusionsThis study derived MCTs for EORTC QLQ-C30 and QLQ-LC13 domains that may be applied in future studies and again demonstrated the superiority of brigatinib over crizotinib in health-related QoL outcomes in patients with non–small cell lung cancer.

Determining the Minimal Clinically Important Difference of the FACT-E to Evaluate the Change in the Quality of Life of Patients with Esophageal Cancer Treated with Curative Radiotherapy

Patients with esophageal cancer (EC) are often treated with radiotherapy (RT). The Functional Assessment of Cancer Therapy-Esophageal (FACT-E) is a health-related quality of life (QOL) instrument validated in patients with EC. The aim of this study was to determine the minimal clinically important difference (MCID) for FACT-E subscales, to allow for meaningful evaluation of the effect of RT on EC patient's QOL. We evaluated patients with EC, treated with curative intent RT, who completed the FACT-E at baseline and end of treatment (EOT). We calculated the MCID for the FACT-E subscales using anchor-based and distribution-based approaches. In the anchor-based approach we determined improvement and deterioration based on the overall health assessment from the PROMIS-10 as the anchor. We modeled the change in domain scores with age-adjusted regressions to determine the difference in classifications. For distribution-based analysis, we considered 0.3 and 0.5 standard deviation (SD). We averaged MCID for improvement and deterioration separately across timepoints, by approach, and we report MCID ranges as the minimum and maximum values across methods. Our cohort included 210 patients with EC, 96.7% white, 85.7% males, and 32.9% treated with photon with a median dose of 50 Gy (IQR 50-50) and a median fraction number of 25(IQR 25,25). The median age at RT was 67.6 years (IQR 60.9,73.7). The social domain had the lowest MCID (deterioration and improvement 0.9-1.9), while the widest MCID range, proportionally to the measure, was associated with the Fact-E total score (2.1-5.6 for improvement, and 3.7-5.6 for deterioration). MCID estimates from 0.3 SD were in exact agreement with the anchor-based deterioration estimates for the physical domain (2.3), and improvement estimates for the Trial Outcome Index (6.1). We determined the MCID for the FACT-E domains, using a combination of anchor- and distribution-based approaches. These findings are critical to determine whether there is meaningful change in the QOL of individuals with EC treated with curative RT.

Determining the Minimal Clinically Important Difference of the Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire to Evaluate the Change in the Quality of Life of Patients With Pancreatic Cancer During Radiation Therapy

This study aimed to define the minimal clinically important difference (MCID) for the FACT Hepatobiliary (FACT-Hep) questionnaire, allowing meaningful evaluation of the effect of radiotherapy (RT) on quality of life (QOL) in patients treated for pancreatic cancer (PC). The cohort included patients with PC who received RT as a component of curative intent therapy, who completed the FACT-Hep at baseline and end of treatment (EOT). The MCID was determined for the FACT-Hep and subdomains using anchor-based and distribution-based approaches. In the anchor-based approach, improvement and deterioration in age-adjusted regression models for change in scores were defined using the overall health assessment item of the PROMIS-10 as the anchor. The MCID was calculated as 0.3 and 0.5 standard deviation (SD) for distribution-based analysis. MCID point estimate using 0.5 SD (range) was averaged across time points and by approach, and the ranges are reported as minimum and maximum values across methods. The FACT-Hep domain with the lowest MCID was the emotional domain (deterioration 0.8-1.8). The hepatobiliary cancer subscale (HCS) has the highest and widest MCID range. A positive change of 2.9-4.3 in HCS should be considered a clinically relevant improvement. MCID estimates from 0.3 SD were in exact agreement with the anchor-based estimates for the physical domain (1.6-2.4). The MCID range for the Fact-Hep total score was 6.9-10.5 and 6.5-10.5 for improvement and deterioration, respectively. The MCID for the FACT-Hep subdomains and totals were calculated using a combination of anchor- and distribution-based approaches. These findings are fundamental to determine whether there is meaningful improvement or deterioration in QOL for patients with PC receiving RT. Evaluating a different anchor for determining the MCID of the social domain is recommended.

Minimal clinically important difference of the Functional Living Index-Emesis in patients with gynecological malignant tumor: A post hoc analysis of a single-arm study.

This study aimed to explore the impact of minimum clinically important difference (MCID) of the Functional Living Index-Emesis (FLIE) in patients with gynecologic malignancies. This post hoc analysis included patients with gynecological malignant tumors in the Department of Oncology of our hospital between October 2020 and October 2021. A total of 149 patients (aged 50.05 ± 12.24 years) were included. Most of the patients were married (75.8%), lived in the city (60.4%), and had a history of motion sickness (75.8%). The degree of nausea (9.00 [0.00, 16.00] vs. 30.00 [16.00, 48.00], P < 0.001) and vomiting (9.00 [0.00, 16.00] vs. 30.00 [16.00, 48.00], P < 0.001) were significantly improved after treatment. Taking the options in the scale as the subjective anchor, the MCID of FLIE for nausea and vomiting were 28.5 and 29 in anchor-based analysis, respectively. In the distribution-based analysis, the MCID of FLIE for nausea and vomiting were 2.41, 6.04, and 9.66; and 2.31, 5.78, and 9.24 in effect size of 0.2, 0.5, and 0.8, respectively. The MCID of FLIE for nausea and vomiting in patients with gynecological malignant tumors was 28.5 and 29 in the anchor-based analysis, with higher specificity, and 6.04 and 5.78 in the distribution-based analysis, with higher sensitivity. The development of the MCID scale might be used to interpret the clinical significance of chemotherapy-induced nausea and vomiting in patients with gynecological malignancies and help to calculate the sample size for future clinical trials.

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients.

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%. This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023.

Determining the clinical significance of the PROMIS physical function score in the setting of femur fractures.

To adequately utilize patient reported outcome scores in the clinical setting, accurate determination of a cohort-specific minimal clinically important differences (MCID) is necessary. The purpose of this study was to assess MCID for Patient Reported Outcome Information System Physical Function Scores (PROMIS®) Physical Function (PF) in a sample of patients who have undergone operative fixation for femur fractures. All patients at a single Level 1 trauma center who were treated for operative femur fractures were identified by Current Procedural Terminology (CPT) codes (27,244, 27,245, 27,506, 27,507). PROMIS PF was collected as part of routine clinical care via computer adaptive testing (CAT). MCID calculations were performed using both anchor-based and distribution-based methods. A total of 182 patients with 723 score observations were included in the overall distribution-based analysis and 131 patients with 309 score observations were included in the anchor-based analysis. In the overall cohort, the average age was 53.1 (SD 22.3), and 45% of participants were female. MCID for PROMIS PF scores was 5.43 in the distribution-based method and 5.18 in the anchor-based method. Overall scores in the distribution group improved from mean of 27.4 (SD 7.0) at the first postoperative visit to a mean of 36.7 (SD 10.0) at a subsequent follow up visit. Overall scores in the anchor group improved from mean of 26.7 (SD 7.3) at the first postoperative visit to a mean of 37.5 (SD 9.3) at a subsequent follow up visit. This study identifies two MCID values (5.18, 5.43) based on two calculation methods for PROMIS physical function scores in the operative femur fracture population. This data could be helpful in targeting postoperative patients who fall below expected norms or in allowing clinical correlation with changes in surgical practice.

Awake endoscopic (esophageal) ultrasound using the endobronchial scope (EUS-B) for patients with high risk for sedation

COPD patients have more fear of falling (FOF) in comparison with control population. One major aim of pulmonary rehabilitation (PR) is to maintain physical activity. Studies show that FOF can limit physical activity. The aim of this study was to assess the impact of PR on FOF in patients with COPD.From January to august 2019, COPD patients (stage 2 to 4) undergoing a 4-weeks PR Program (PRP) at Morlaix Hospital Centre were included in this prospective observational study. The objectives were to assess [1] the impact of PR on FOF, [2] the correlations between evolution of FOF and evolution of parameters usually used during PRP, [3] to determine a MID for FOF. The primary endpoint was the Fall Efficacy Scale-International (FES-I) questionnaire. The secondary endpoints were tests and questionnaires usually used to assess exercise capacity, quality of life, dyspnea, anxiety, depression, and balance.80 patients were included and 72 were analysed. After the PRP, there was a significant decrease of FOF, with significative decrease of FES-I score (−3.36, p<0.001) CI 95% [−5.1; −1.6]). The evolution of FES-I score was moderately correlated to changes in quality of life (QOL) using CAT (Intra-class Correlation Coefficient (ICC)=0.340, p=0.005) and SGRQ (ICC=0.454, p<0.0001), dyspnea using MMRC (ICC=0.311, p=0.009) and LCADL (ICC=0.396, p=0.001); and weakly correlated to changes in balance (ICC=−0.280, p=0.026). Using the distribution-based analysis, we found a MID between −3.6 to –4.9.We showed a significant decrease of fear of falling in COPD patients after PRP, correlated with improvement of QOL, balance and decrease of dyspnea. We propose a MID of −4.9 for FES-I.ClinicalTrials.gov NCT03793452

Effects of pulmonary rehabilitation on fear of falling in Chronic Obstructive Pulmonary Disease (COPD) patients: An observational study

ObjectiveCOPD patients have more fear of falling (FOF) in comparison with control population. One major aim of pulmonary rehabilitation (PR) is to maintain physical activity. Studies show that FOF can limit physical activity. The aim of this study was to assess the impact of PR on FOF in patients with COPD. MethodsFrom January to august 2019, COPD patients (stage 2 to 4) undergoing a 4-weeks PR Program (PRP) at Morlaix Hospital Centre were included in this prospective observational study. The objectives were to assess [1] the impact of PR on FOF, [2] the correlations between evolution of FOF and evolution of parameters usually used during PRP, [3] to determine a MID for FOF. The primary endpoint was the Fall Efficacy Scale-International (FES-I) questionnaire. The secondary endpoints were tests and questionnaires usually used to assess exercise capacity, quality of life, dyspnea, anxiety, depression, and balance. Results80 patients were included and 72 were analysed. After the PRP, there was a significant decrease of FOF, with significative decrease of FES-I score (−3.36, p<0.001) CI 95% [−5.1; −1.6]). The evolution of FES-I score was moderately correlated to changes in quality of life (QOL) using CAT (Intra-class Correlation Coefficient (ICC)=0.340, p=0.005) and SGRQ (ICC=0.454, p<0.0001), dyspnea using MMRC (ICC=0.311, p=0.009) and LCADL (ICC=0.396, p=0.001); and weakly correlated to changes in balance (ICC=−0.280, p=0.026). Using the distribution-based analysis, we found a MID between −3.6 to –4.9. ConclusionWe showed a significant decrease of fear of falling in COPD patients after PRP, correlated with improvement of QOL, balance and decrease of dyspnea. We propose a MID of −4.9 for FES-I. Trial RegistrationClinicalTrials.gov NCT03793452

Minimal Clinically Important Differences of PROMIS PF in Ankle Fracture Patients.

Evaluating the minimal clinically important differences (MCIDs) in patient-reported outcome scores is essential for use of clinical outcomes data. The purpose of the current study was to calculate MCID of Patient Reported Outcome Information System Physical Function (PROMIS PF) scores for ankle fracture patients. All patients who underwent operative fixation for ankle fractures at a single level 1 trauma center were identified by Current Procedural Terminology code. PROMIS PF scores were collected. Patients had to complete an anchor question at 2 time points postoperatively to be included in this study. Anchor-based and distribution-based MCIDs were calculated. A total of 331 patients were included in the distribution-based analysis, and 195 patients were included in the anchor-based analysis. Mean age was 45.3 years (SD 17.5), and 59.4% of participants were female. MCID for PROMIS PF scores was 5.05 in the distribution-based method and 5.43 in the anchor-based method. This study identified MCID values based on 2 time points postoperatively for PROMIS PF scores in the ankle fracture population. Both methods of MCID calculation resulted in equivalent MCIDs. This can be used to identify patients outside the normal preoperative and postoperative norms and may help to make clinically relevant practice decisions. Level I, diagnostic study, testing of previously developed diagnostic measure on consecutive patients with reference standard applied.

Weibull distribution-based analysis for reliability assessment of an isolated power micro-grid system

This study investigates Weibull Distribution-based Analysis for reliability assessment of an isolated power Micro-grid system. The Mean Time to Repair (MTTR) reliability indices were calculated using the outage data obtained from the micro-grid site between 2015 and 2019. The Weibull probability function is widely used in reliability analysis; in this method, the shape and scale parameters were calculated using the Maximum likelihood Estimator (MLE). MLE technique was deployed to check the problem of the MTTR data analysis from data collected to estimate the Weibull study. The research involved the percentage, cumulative percentage, density, cumulative probability, survival probability, and hazard probability. The scale parameter, which was observed as 0.625195, equally represents the mean failure time of 0.99728, which influenced the overall reliability performance of the micro-grid power system.

Distribution-based packet forwarding distance dissimilarity learning for topology characterizing in geographic routing

Abstract We have previously shown that the geographic routing’s greedy packet forwarding distance (PFD), in dissimilarity values of its average measures, characterizes a mobile ad hoc network’s (MANET) topology by node size. In this article, we demonstrate a distribution-based analysis of the PFD measures that were generated by two representative greedy algorithms, namely GREEDY and ELLIPSOID. The result shows the potential of the distribution-based dissimilarity learning of the PFD in topology characterizing. Characterizing dynamic MANET topology supports context-aware performance optimization in position-based or geographic packet routing.

The relationship between protein intake and gut microbiota in community-dwelling older men from the MrOS study.

Older patients with traumatic brain injury (TBI) have higher mortality and poorer long-term outlook compared to younger individuals. This may contribute to the assumption that aggressive management of geriatric TBI is futile. The present study examined the long-term recovery potential and underlying mechanisms associated with advanced age in male C57BL/6 mice using a controlled cortical impact model of TBI. Older (18 mos) mice had higher mortality compared to younger (10 wks) mice at 12 weeks post-injury. While aging alone had a profound impact on behavioral ability, the recovery slope in some, but not all, neurobehavioral tests was relatively similar between young and old injured mice. NanoString analysis identified several age- and injury-specific genes that were differentially expressed, including those involved with the complement, phagocytosis, and autophagy pathways. Flow cytometry demonstrated dysregulation of autophagic function in microglia with normal aging which was exacerbated after TBI. Given the critical role for autophagy in promoting the cellular degradation of cytoplasmic materials, we reasoned that treatment with the autophagic inducer, trehalose, may be a viable therapeutic strategy. Trehalose was administered in the drinking water (3%) starting at d1 post-injury up to 8 weeks. Older TBI mice treated with trehalose exhibited either delayed deficits or enhanced recovery in cognitive and motor tasks. Trehalose modified expression of autophagy markers and reprogrammed the microglial response to TBI. Our data indicate that microglia undergo chronic changes in autophagic regulation that are associated with poor outcome. Boosting autophagy may be a promising therapeutic strategy for older TBI patients.

The Minimal Clinically Important Difference: A Review of Clinical Significance

Background: The minimal clinically important difference (MCID) is a term synonymous with orthopaedic clinical research over the past decade. The term represents the smallest change in a patient-reported outcome measure that is of genuine clinical value to patients. It has been derived in a myriad of ways in existing orthopaedic literature. Purpose: To describe the various modalities for deriving the MCID. Study Design: Narrative review; Level of evidence, 4. Methods: The definitions of common MCID determinations were first identified. These were then evaluated by their clinical and statistical merits and limitations. Results: There are 3 primary ways for determining the MCID: anchor-based analysis, distribution-based analysis, and sensitivity- and specificity-based analysis. Each has unique strengths and weaknesses with respect to its ability to evaluate the patient’s clinical status change from baseline to posttreatment. Anchor-based analyses are inherently tied to clinical status yet lack standardization. Distribution-based analyses are the opposite, with strong foundations in statistics, yet they fail to adequately address the clinical status change. Sensitivity and specificity analyses offer a compromise of the other methodologies but still rely on a somewhat arbitrarily defined global transition question. Conclusion: This current concepts review demonstrates the need for (1) better standardization in the establishment of MCIDs for orthopaedic patient-reported outcome measures and (2) better study design—namely, until a universally accepted MCID derivation exists, studies attempting to derive the MCID should utilize the anchor-based within-cohort design based on Food and Drug Administration recommendations. Ideally, large studies reporting the MCID as an outcome will also derive the value for their populations. It is important to consider that there may be reasonable replacements for current derivations of the MCID. As such, future research should consider an alternative threshold score with a more universal method of derivation.

Evaluation of approaches to estimate discharge indices based on mean sediment load for suspended sediment transport in South Indian catchments

ABSTRACT Discharge indices based on mean sediment load such as fraction-load (f-load) discharge and functional-equivalent discharge represent long-term sediment transfer through river networks. These discharge indices can be used as design flows for the restoration of river channels and in geomorphic and eco-hydrologic studies. In this paper, lognormal distribution-based and Gamma distribution-based Magnitude-Frequency Analysis (MFA) approaches are evaluated to determine reliable estimates of discharge indices for suspended sediment transport in South Indian catchments. The discharge indices are estimated by considering (i) total suspended sediment load and (ii) fine, medium, and coarse suspended sediment loads, separately, as various fractions of suspended sediments have different hydraulic characteristics, transport behaviour, and effect on the ecological system. Results indicate that the lognormal distribution being heavy-tailed tends to assign considerable frequency densities to higher discharges which results in unreliable and magnified estimates of mean sediment load and subsequent discharge indices for most of the catchments. Overall, the Gamma distribution-based MFA approach is found to yield reliable estimates of the f-load discharge and functional-equivalent discharge in comparison to the lognormal distribution-based MFA approach.

Variance-based global sensitivity analysis and beyond in life cycle assessment: an application to geothermal heating networks

PurposeGlobal sensitivity analysis increasingly replaces manual sensitivity analysis in life cycle assessment (LCA). Variance-based global sensitivity analysis identifies influential uncertain model input parameters by estimating so-called Sobol indices that represent each parameter’s contribution to the variance in model output. However, this technique can potentially be unreliable when analyzing non-normal model outputs, and it does not inform analysts about specific values of the model input or output that may be decision-relevant. We demonstrate three emerging methods that build on variance-based global sensitivity analysis and that can provide new insights on uncertainty in typical LCA applications that present non-normal output distributions, trade-offs between environmental impacts, and interactions between model inputs.MethodsTo identify influential model inputs, trade-offs, and decision-relevant interactions, we implement techniques for distribution-based global sensitivity analysis (PAWN technique), spectral clustering, and scenario discovery (patient rule induction method: PRIM). We choose these techniques because they are applicable with generic Monte Carlo sampling and common LCA software. We compare these techniques with variance-based Sobol indices, using a previously published LCA case study of geothermal heating networks. We assess eight environmental impacts under uncertainty for three design alternatives, spanning different geothermal production temperatures and heating network configurations.ResultsIn the application case on geothermal heating networks, PAWN distribution-based sensitivity indices generally identify influential model parameters consistently with Sobol indices. However, some discrepancies highlight the potentially misleading interpretation of Sobol indices on the non-normal distributions obtained in our analysis, where variance may not meaningfully describe uncertainty. Spectral clustering highlights groups of model results that present different trade-offs between environmental impacts. Compared to second-order Sobol interaction indices, PRIM then provides more precise information regarding the combinations of input values associated with these different groups of calculated impacts. PAWN indices, spectral clustering, and PRIM have a computational advantage because they yield stable results at relatively small sample sizes (n = 12,000), unlike Sobol indices (n = 100,000 for second-order indices).ConclusionsWe recommend adding these new techniques to global sensitivity analysis in LCA as they give more precise as well as additional insights on uncertainty regardless of the distribution of the model outputs. PAWN distribution-based global sensitivity analysis provides a computationally efficient assessment of input sensitivities as compared to variance-based global sensitivity analysis. The combination of clustering and scenario discovery enables analysts to precisely identify combinations of input parameters or uncertainties associated with different outcomes of environmental impacts.

DiBAC: Distribution-Based Analysis of Cell Differentiation Identifies Mechanisms of Cell Fate

The recent developments in single cell genomics allow for in-depth characterization of cellular heterogeneity in tissue development and the identification of new regulatory mechanisms. Despite these achievements, our understanding of underlying principles in cell fate dynamics is still rather limited. Here, we present a new approach that exploits the high dimensional transcription distributions of single cell RNA sequencing (sc-RNAseq) data by information theorybased measures, which allow for robust identification of cell differentiation properties and efficient differentially expressed gene (DEG) analysis. We show that appropriate binarization of single cell transcription data allows for the rigorous definition of mutual information and robust entropy measures that reflect the general properties of cell fate decisions. We exemplify our distribution-based analysis of cell differentiation (DiBAC) with single cell qPCR data of blood cell development and sc-RNAseq data of Parkinson’s disease-related iPSC differentiation into dopaminergic neurons.

Determination of the minimal important difference for Dyspnoea-12 questionnaire in patients with COPD, after pulmonary rehabilitation.

The authors of the international task force about the management of Dyspnoea recommend assessing sensory and affective components of dyspnoea. The Dyspnoea-12 questionnaire (D-12) allows to assess both components of dyspnoea. D-12 is valid and reliable but its sensitivity to pulmonary rehabilitation was not studied. The aim of this study was to estimate the minimal important difference (MID) for D-12 in COPD patients undergoing a pulmonary rehabilitation programme (PRP). Severe or very severe COPD patients undergoing a PRP were included. Dyspnoea was assessed using D-12, MMRC dyspnoea scale, London chest of Activity of Daily Living questionnaire (LCADL). Quality of life was assessed using Saint-George respiratory questionnaire (SGRQ) and COPD assessment Test (CAT); exercise capacity using 6-Minute walk Test (6MWT) and 1-minute sit to-stand test (1STST). The MID was evaluated using distribution and anchor-based methods. Sixty patients (age: 64.4±8.2; FEV1(%): 28.6±8.1) were included. At the end of the PRP, patients had significantly decreased their dyspnoea measured with D-12, MMRC, LCADL (D-12:23.9±8.9 to 17.6±9.4; MMRC: 3±0.7 to 2.2±1.1, LCADL: 38±13.9 to 31.6±11; p<0.0001). Using the distribution-based analysis, MID of -2.67 (standard error of measurement) or -4.45 (standard deviation) was found. According to methodology, we could only use SGRQ as anchor. With SGRQ as anchor, the receiver operating characteristic curve identified MID for the change in D-12 at -6.1 (sensibility: 58%, specificity: 79%). The correlation with SGRQ was modest (r=0.33), so the calculated MID should be interpreted with caution. D-12 is a good tool to assess the decrease of dyspnoea after PR. We propose MID of -6 points. However, Future estimates of MID for the D-12 should use anchors that are more strongly correlated with it.

PIH76 ITCH REPORTED OUTCOME TOOL FOR CAREGIVERS OF PEDIATRIC PATIENTS WITH CHOLESTATIC LIVER DISEASE: AN ANALYSIS OF VALIDATION AND SCORING FROM THE ICONIC MARALIXIBAT STUDY

The Itch Reported Outcome tool for observers (ItchRO[Obs]) was developed specifically to assess the severity of itch-related symptoms in children with cholestatic liver disease, including Alagille syndrome (ALGS). Itch is evaluated daily in the morning (AM) and evening (PM) using a five-point scale of itch severity (0=none, 4=most severe itch). This study evaluated the psychometric properties of the ItchRO(Obs) in the ICONIC study. Data from ICONIC, a maralixibat 48-week phase 2 placebo-controlled, randomized withdrawal study (RW) in children with ALGS were analyzed. Scores were generated by taking the average of the AM or PM responses over a 7- or 28-day period. Validity and reliability analyses of both the AM and PM scores were conducted. Concurrent and known-groups validity of the new ItchRO scores were examined against co-validators (i.e., Clinician Scratch Scale [CSS] and the caregiver-reported Pediatric Quality of Life Inventory [PedsQL]). Distribution-based and anchor-based approaches were used to establish the clinically relevant minimally important difference (MID). Positive correlations between ItchRO(Obs) and CSS scores indicated convergent validity, with correlations ranging from r = 0.63 to 0.78. Negative correlations between ItchRO and PedsQL scores indicated divergent validity, with correlations ranging from r = -0.1 to -0.96. Known-groups validity analysis showed worse ItchRO(Obs) scores were associated with more damage of the skin due to pruritus, as measured by the CSS, confirming that ItchRO(Obs) scores are consistent with worsening pruritus. Distribution-based analysis for a MID showed the estimated standard error of measurement (SEM) ranged from 0.28 to 0.32. Using a criterion of 2 SEMs as the MID, these results indicated 7- and 28-day AM and PM change scores of -0.56 to -0.64 were indicative of clinically relevant changes in pruritus. ItchRO(Obs) is reliable, valid and capable of detecting small clinically meaningful changes in pruritus-related symptoms as reported by caregivers of patients with ALGS.

Strength of graphene with curvilinear grain boundaries

Understanding the mechanical properties of grain boundaries (GB) in graphene is critical to commercial realization of large-area graphene in a vast array of applications. Previous pursuits on this topic mainly deal with tilt GBs, overlooking rotational GBs. Rotational GBs are composed of pentagon-heptagon pairs and are observed in mass-produced graphene. Herein, molecular dynamics simulations were conducted to determine the effect of GB curvature on the mechanical properties of graphene. While there was minimal effect on the Young’s Modulus (less than 5%), a Weibull distribution-based analysis revealed weakening of strength and strain to failure with decreasing grain boundary curvature (by up to 23 GPa). Mechanical failure in rotational GBs was observed to occur by catastrophic failure of C–C bonds parallel to the tensile axis either away from or on the GB, differing by the initiating failure event depending on GB curvature. At higher GB curvatures, initial failure occurred in the bulk away from the GB. At lower GB curvatures, however, failure was initiated by a pseudo-plastic bond rotation, which propagated to catastrophic failure under increasing applied stress. Mitigation of crack propagation at lower curvatures was observed by the formation of monoatomic carbon chains, prolonging material survival under an applied stress.