Extreme Weights Research Articles

Pharmacokinetics and Pharmacodynamics of Meropenem by Extended or Continuous Infusion in Low Body Weight Critically Ill Patients.

Background: Pathophysiological changes such as extreme body weights in critically ill patients with severe infections may alter the pharmacokinetics (PK) of antimicrobials, leading to treatment failure or toxicity. There are almost no PK data on meropenem in critically ill patients with low body weight (LwBW) and therefore information is lacking on the most appropriate dosing regimens, especially when administered by extended infusion. Objectives: To assess if the current administered doses of meropenem could lead to supratherapeutic concentrations in LwBW patients and to identify the factors independently associated with overexposure. Methods: A matched case-control 1:1 study of surgical critically ill patients treated with meropenem administered by extended or continuous infusion and undergoing therapeutic drug monitoring was conducted. Cases (patients with LwBW (body mass index (BMI) < 18.5 kg/m2)) were matched with normal body weight controls (NBW) (patients with BMI ≥ 18.5 kg/m2 and ≤30 kg/m2)) by age, gender, baseline renal function and severity status (APACHE II score). A 100% fT > MIC was considered an optimal pharmacokinetic/pharmacodynamic (PK/PD) target and 100% fT > 10 × MIC as supratherapeutic exposure. Results: Thirty-six patients (18 cases and 18 controls) were included (median (range) age, 57.5 (26–75) years; 20 (55.6% male)). Meropenem was administered by 6 h (extended) or 8 h (continuous) infusion at a median (range) daily dose of 5 (1–6) g/day. Similar median meropenem trough plasma concentrations (Cmin,ss), measured pre-dose on day three to four of treatment) were observed in the two groups (19.9 (22.2) mg/L vs 22.4 (25.8) mg/L, p > 0.999). No differences in the proportion of patients with an optimal or a supratherapeutic PKPD target between cases and controls were observed. A baseline estimated glomerular filtration rate (eGFR) < 90 mL/min was the only factor independently associated with a supratherapeutic PK/PD target. Conclusions: LwBW seems not to be a risk factor for achieving a supratherapeutic PK/PD target in critically ill patients receiving meropenem at standard doses by extended or continuous infusion.

Transaction and interaction behavior-based consensus model and its application to optimal carbon emission reduction

Consensus is an essential issue in group decision making (GDM) research, since inability to reach a consensus may lead to a costly decision paralysis. Generally, in real GDM scenarios, some interaction between decision makers (DMs) is effective at promoting consensus. The Choquet integral is a proper mathematical tool for integrating information while considering both interaction and fusion. This is why in this paper, we apply the Choquet integral to model a transaction and interaction behavior-based consensus. In the proposed model, we define the weights and interaction indices of DMs in an interactive environment to avoid extreme discourse weights. Subsequently, we apply the optimal consensus model to the trade of discourse weights in carbon emission reduction. Simultaneously, we consider the inter-group transactions between discourse weights and individual weight restriction behaviors. A case study with weight transfers reveals that, compared to the traditional consensus optimization model with minimum costs, the proposed novel transaction and interaction behavior-based consensus model has a broader scope of application. It not only reflects the fairness of the consensus results, but it also achieves better decision-making results.

Health-Related Quality of Life across Recent Pediatric Obesity Classification Recommendations.

Extreme body mass index (BMI) values (i.e., above the 97th and below the 3rd percentiles) are inaccurately represented on the Centers for Disease Control and Prevention’s growth curves, which may limit the utility of BMI percentile and BMI z-score for capturing changes in clinical outcomes for patients at extreme weights. Modeling child obesity severity based upon the percentage of BMI in excess of the 95th percentile (BMI95pct) has been proposed as an improved metric to better capture variability in weight at extreme ends of growth curves, which may improve our understanding of relationships between weight status and changes in clinical outcomes. However, few studies have evaluated whether the use of BMI95pct would refine our understanding of differences in clinical psychosocial constructs compared to previous methods for categorization. This cross-sectional study evaluated child obesity severity based on BMI95pct to examine potential group differences in a validated, obesity-specific measure of Health-Related Quality of Life (HRQoL). Four hundred and sixty-five children with obesity completed Sizing Me Up, a self-report measure of HRQoL. Children were classified into categories based on BMI95pct (i.e., class I: ≥100% and <120%; class II: ≥120% and <140%; class III: ≥140%). The results indicate that children with class III obesity reported lower HRQoL than children with class I and class II obesity; however, there were no differences between Class II and Class I. In much of the previous literature, children with class II and class III obesity are often combined under the category “Severe Obesity” based upon BMI above the 99th percentile. This study suggests that grouping children from various classes together would neglect to capture critical differences in HRQoL. Future research including children with severe obesity should consider obesity classes to best account for functioning and clinical outcomes.

Observer Influence with Other Variables on the Accuracy of Ultrasound Estimation of Fetal Weight at Term.

Background and Objectives: The accuracy with which the estimation of fetal weight (EFW) at term is determined is useful in order to address obstetric complications, since it is a parameter that represents an important prognostic factor for perinatal and maternal morbidity and mortality. The aim of this study was to determine the role of the experienced observers with other variables that could influence the accuracy of the ultrasound used to calculate EFW at term, carried out within a period of seven days prior to delivery, in order to assess interobserver variability. Materials and Methods: A cross-sectional study was performed including 1144 pregnancies at term. The validity of the ultrasound used to calculate EFW at term was analyzed using simple error, absolute error, percentage error and absolute percentage error, as well as the percentage of predictions with an error less than 10 and 15% in relation to maternal, obstetric and ultrasound variables. Results: Valid predictions with an error less than 10 and 15% were 74.7 and 89.7% respectively, with such precision decreasing according to the observer as well as in extreme fetal weights. The remaining variables were not significant in ultrasound EFW at term. The simple error, absolute error, percentage error and absolute percentage error were greater in cases of extreme fetal weights, with a tendency to overestimate the low weights and underestimate the high weights. Conclusions: The accuracy of EFW with ultrasound carried out within seven days prior to birth is not affected by maternal or obstetric variables, or by the time interval between the ultrasound and delivery. However, accuracy was reduced by the observers and in extreme fetal weights.

Restricted calibration and weight trimming approaches for estimation of the population total in business statistics

Some adjustments are made to design weights to reduce the negative effects of non-response and out-of-scope problems. The calibration approach is a weighting process that agrees with the known population values by using auxiliary information. In this study, alternative calibration approaches and weight trimming process that can be used in large data sets with extreme weights and different correlation structures were analysed. In addition, the effect of the correlation structure of auxiliary variables on the efficiency of the calibration estimators was investigated by a simulation study. The 2017 Annual Industry and Service Statistics data were used in the simulation study and it was seen that restricted calibration estimators were more efficient than the generalized regression estimator in estimating the variables with a high variance such as turnover. Especially in small sample fractions, we recommend the application of restricted calibration estimators, as they are more efficient than the weight trimming in solving the negative and less than one weights problem encountered after the calibration process.

Safety and efficacy of direct oral anticoagulants across body mass index groups in patients with venous thromboembolism: a retrospective cohort design.

Current literature on the safety and efficacy of direct oral anticoagulants (DOACs) in patients of extreme weights are limited, however, they are still being prescribed in these populations. The objective of this study is todescribe the safety and efficacy of DOAC therapy in patients of extreme weights for the treatment of venous thromboembolism (VTE) using body mass index (BMI) groups. A multi-site, retrospective cohort design at four hospitals was performed. Patients who experienced an initial VTE between November 2012 and August 2017 and placed on a DOAC were included. Patients were defined as: extremely obese (EO) if BMI ≥ 40kg/m2, obese if BMI 30-39.9kg/m2, normal/overweight if BMI 18.5-29.9kg/m2, and underweight if BMI < 18.5kg/m2. The primary efficacy outcome of recurrent VTE and primary safety outcome of major bleeding (MB) within 12months were compared between weights. Univariate statistical tests and multivariate logistic regression analyses were performed. Rates of recurrent VTE showed no significant differences (p = 0.58) across groups; 7.8% (11/142) EO, 4.7% (18/383) obese, 5.2% (27/517) normal/overweight, and 5.9% (1/17) underweight. Proportions of MB were overall significantly different (p = 0.026); 6.3% (9/142) EO, 10.4% (40/383) obese, 10.1% (52/517) normal/overweight, and 29.4% (5/17) underweight. EO and obese patients had similar odds of MB compared to normal/overweight (OR 0.61, 95% CI [0.29, 1.26] and OR 1.04, 95% CI [0.67, 1.61]). Underweight patients showed larger odds of MB compared to normal/overweight (OR 3.73, 95% CI [1.26, 11.0]). This study found that recurrence of VTE was not associated with BMI. However, the proportions of major bleeding were statistically different among the BMI categories.

Critical Analysis of Apixaban Dose Adjustment Criteria.

Apixaban is indicated for the prevention of ischemic stroke in non-valvular atrial fibrillation (NVAF), as well as for the prevention and treatment of venous thromboembolism (VTE). Dose adjustment is based on age, weight, and serum creatinine in NVAF, while there are no recommended adjustment criteria for VTE. Such adjustment is unconventional compared to other commonly used medications. The objective of this manuscript is to critically analyze each apixaban dosing adjustment criterion and its associated outcomes. PubMed articles from March 2013 to March 2020 were selected with search terms “apixaban,” and “dose adjustment,” “adjustment,” or “adjustment criteria.” Pharmacokinetic studies demonstrated increased apixaban exposure in patients >65 years of age, those with extreme body weights, and those with advanced renal impairment, though post-hemodialysis dosing may off-set the elevated apixaban exposure. However, clinical data show that among patients >75 years, <60 kg, and with estimated glomerular filtration rate <50 mL/min, including those on dialysis, there is no reduction in apixaban safety or efficacy. Published literature describes variable dosing strategies utilized in clinical practice. Overall, apixaban dose adjustment criteria may need to be re-evaluated.

Propensity score stratification methods for continuous treatments.

Continuous treatments propensity scoring remains understudied as the majority of methods are focused on the binary treatment setting. Current propensity score methods for continuous treatments typically rely on weighting in order to produce causal estimates. It has been shown that in some continuous treatment settings, weighting methods can result in worse covariate balance than had no adjustments been made to the data. Furthermore, weighting is not always stable, and resultant estimates may be unreliable due to extreme weights. These issues motivate the current development of novel propensity score stratification techniques to be used with continuous treatments. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) and the nonparametric GPS-CDF approaches are introduced. Empirical CDFs are used to stratify subjects based on pretreatment confounders in order to produce causal estimates. A detailed simulation study shows superiority of these new stratification methods based on the empirical CDF, when compared with standard weighting techniques. The proposed methods are applied to the "Mexican-American Tobacco use in Children" study to determine the causal relationship between continuous exposure to smoking imagery in movies, and smoking behavior among Mexican-American adolescents. These promising results provide investigators with new options for implementing continuous treatment propensity scoring.

Cardiac Output Measurement With Echocardiography and Pressure Recording Analytical Method in Pediatric Patients Admitted to the Cardiac Intensive Care Unit: A Retrospective Assessment of Bias Between the Two Methods

This study aimed to compare, in a cohort of critically ill children with biventricular anatomy and no cardiovascular shunt, cardiac output (CO) and cardiac index (CI) assessed by echocardiography and a continuous pulse-contour method, MostCareUP, to measure the differences between these techniques (biasCO and biasCI), and their association with clinical variables. Retrospective study. Tertiary pediatric cardiac intensive care unit. Children admitted to the pediatric cardiac intensive care unit who underwent echocardiography with CO measurement. None. Thirty-five patients were included. BiasCO was -0.02 (0.26) L/min (percentage error 36%). BiasCI was 0.07 (0.34) L/min/m2 (percentage error 18%). Biases and percentage errors were higher in 24 nonsupervised echocardiographies. A negative biasCO (overestimation by MostCareUP) was associated with post-surgical status (v cardiomyopathy), higher systolic arterial pressure, and spontaneous breathing (v intubation). When only absolute values were considered, biasCONONEG correlated with age, weight, arterial pressure, and heart rate, whereas biasCINONEG was associated with a femoral arterial cannula, no use of inotropes, and the absence of mechanical ventilation. After adjustment, biasCONONEG remained independently associated with patients' body weight(p = 0.0001). BiasCINONEG showed a nonlinear relationship with weight below 20 kg and above 40 kg. Children with extreme low or high weights, those who are extubated, and those with a femoral cannula carry the highest bias. When younger patients are considered, CI should be evaluated instead of CO, because biases are better highlighted by indexing data on body surface area. In children, both echocardiography and MostCareUP may be responsible of inaccurate CO/CI assessment.

Potential of Artificial Intelligence for Estimating Japanese Fetal Weights.

We developed an artificial intelligence (AI) method for estimating fetal weights of Japanese fetuses based on the gestational weeks and the bi-parietal diameter, abdominal circumference, and femur length. The AI comprised of neural network architecture was trained by deep learning with a dataset that consists of ± 2 standard devia-tion (SD), ± 1.5SD, and ± 0SD categories of the approved standard values of ultrasonic measurements of the fetal weights of Japanese fetuses (Japan Society of Ultrasonics in Medicine [JSUM] data). We investigated the residuals and compared 2 other regression formulae for estimating the fetal weights of Japanese fetuses by t-test and Bland-Altman analyses, respectively. The residuals of the AI for the test dataset that was 12.5% of the JSUM data were 6.4 ± 2.6, -3.8 ± 8.6, and -0.32 ± 6.3 (g) at -2SD, +2SD, and all categories, respectively. The residu-als of another AI method created with all of the JSUM data, of which 20% were randomized validation data, were -1.5 ± 9.4, -2.5 ± 7.3, and -1.1 ± 6.7 (g) for -2SD, +2SD, and all categories, respectively. The residuals of this AI were not different from zero, whereas those of the published formulae differed from zero. Though vali-dation is required, the AI demonstrated potential for generating fetal weights accurately, especially for extreme fetal weights.

Semiparametric estimation for average causal effects using propensity score-based spline

When estimating the average causal effect in observational studies, researchers have to tackle both self-selection of treatment and outcome modeling. This is difficult because the parametric form of the outcome model is often unknown and there exists a large number of covariates. In this work, we present a semiparametric strategy for estimating the average causal effect by regressing on the propensity score. Furthermore, we show that regression error terms usually depend on the propensity score as well, which could cause heteroscedastic variances, and thus construct a refined estimator to improve the estimation efficiency. Both estimators are shown to be consistent and asymptotically normally distributed, with the latter one having a smaller asymptotic variance. The simulation studies indicate that our methods compare favorably with many competing estimators. Our methods are easy to implement and avoid hazardous impact due to extreme weights as often seen in weighting estimators. They can also be extended to handle subgroup effects with known structure. We apply the proposed methods to data from the Ohio Medicaid Assessment Survey 2012, estimating the effect of having health insurance on self-reported health status for a population with subsidized insurance plan choices under the Affordable Care Act.

Efficacy and Safety of Direct Oral Anticoagulants in Extremes Weights

Background: The clinical use of Direct oral anticoagulants (DOACs), as opposed to warfarin, has become more prevalent in patients with extremes in body weight. However, both the International Society on Thrombosis and Haemostasis' (ISTH) and anti-thrombotic therapy guidelines state that DOACs should be avoided in patients with a body mass index (BMI) &amp;gt;40 kg/m2, weight &amp;gt;120 kg, or weight &amp;lt; 50 kg. The purpose of this study was to analyze the efficacy and safety of DOACs in extremes of weight compared to patients treated with warfarin. Warfarin may be a safer and more effective oral anticoagulant for patients in extremes of weight, due to the availability of dosing based on INR. DOAC standard dosing may either overdose/underdose in patients with low/high BMI respectively. Study Design and Methods: A retrospective, single-institution study evaluated patients with extreme weights receiving a DOAC or warfarin for either venous thromboembolism (VTE) or atrial fibrillation/atrial flutter between October 2016 and October 2020. Inclusion criteria consisted of patients admitted to NYU Langone Hospitals continued on a DOAC or warfarin for VTE or atrial fibrillation/atrial flutter with BMI &amp;lt; 18 kg/m2 or BMI &amp;gt; 30 kg/m2. Patients newly initiated on oral anticoagulation or received anticoagulation other than atrial fibrillation/atrial flutter or VTE were excluded. Primary endpoints include incidence of VTE or bleeding events in anticoagulated patients who meet extreme weight criteria. Disclosures No relevant conflicts of interest to declare.

Adipokines Expression and Effects in Oocyte Maturation, Fertilization and Early Embryo Development: Lessons from Mammals and Birds.

Some evidence shows that body mass index in humans and extreme weights in animal models, including avian species, are associated with low in vitro fertilization, bad oocyte quality, and embryo development failures. Adipokines are hormones mainly produced and released by white adipose tissue. They play a key role in the regulation of energy metabolism. However, they are also involved in many other physiological processes including reproductive functions. Indeed, leptin and adiponectin, the most studied adipokines, but also novel adipokines including visfatin and chemerin, are expressed within the reproductive tract and modulate female fertility. Much of the literature has focused on the physiological and pathological roles of these adipokines in ovary, placenta, and uterine functions. The purpose of this review is to summarize the current knowledge regarding the involvement of leptin, adiponectin, visfatin, and chemerin in the oocyte maturation, fertilization, and embryo development in both mammals and birds.

Conditioning of extreme learning machine for noisy data using heuristic optimization

This article provides a tool that can be used in the exact sciences to obtain good approximations to reality when noisy data is inevitable. Two heuristic optimization algorithms are implemented: Simulated Annealing and Particle Swarming for the determination of the extreme learning machine output weights. The first operates in a large search space and at each iteration it probabilistically decides between staying at its current state or moving to another. The swarm of particles, it optimizes a problem from a population of candidate solutions, moving them throughout the search space according to position and speed. The methodology consists of building data sets around a polynomial function, implementing the heuristic algorithms and comparing the errors with the traditional computation method using the Moore–Penrose inverse. The results show that the heuristic optimization algorithms implemented improve the estimation of the output weights when the input have highly noisy data.

Impact of simplified methods of growth recording on genetic parameter estimates of Tunisian local goat population under a low input production system

The study aims to simulate the alternative methods of simplifying weight recording of Tunisian local kids and assesses the impact of their use from a genetic point of view to set up the basis for the future improvement of this important component of efficient production. A total of 13,095 weight records of 945 kids, progeny of 285 females and 19 males were collected over a period of 16 years in the caprine herd of the Arid Areas Institute of Médenine (South East of Tunisia).Weights were taken at six standard ages (10, 30, 60, 90,120 and 150 days) at a weekly pace. Alternative simplified schemes were simulated by skipping from 1–7 weeks of recording and performance in terms of predicting weights at the standard ages was evaluated. In addition, random regression model (RRM) including age of females, interaction sex × type of birth, interaction year × month of birth was used as fixed effects. Also, animal- and maternal permanent environmental as random effects, were fitted to the data set. Alternative simplified recording systems were then evaluated in terms of modifications in estimated genetic parameters and correlations among estimated breeding values. Results showed that 1–3 weeks of time between recordings yielded accurate estimates of weights at the standard ages. The effect of the simplified weight recording was especially relevant at the extreme weights, at 10 and at 150 days of age, that the spacing of successive controls affects the accuracy of the estimate. The lack of registration of birth weight showed a significant deterioration in the estimate of weight at 10 days. Only the simplification of the weights recording to one and two-week resulted in direct and maternal heritability’s for the different growth traits of local kids, similar to those obtained by the standard age growth recording. Selecting the critical ages that define changes in growth components seems to be more critical than using more frequent weighing in terms of estimation of the genetic components of weight of kids in this population. Highlights This type of local kids measurement simplification can be seen as an alternative: ^ To enhance the economical aspect of the sheep recording scheme. ^ Reduce animal disturbance. According to the results of this study, the adoption of a common growth control system seems difficult since the breeding objectives and for farming systems are not the same.

Construction and application of a comprehensive coordination and cross-efficiency sustainable development evaluation model: a case study of 31 provinces and regions in China

This paper proposes a comprehensive coordination and cross-efficiency evaluation model, aimed at tackling the problems evident in self-evaluation systems based on data envelopment assessment models, such as “developing strengths and avoiding weaknesses,” “ranking strengths and weaknesses completely,” extreme weights, and so on. Based on environmental sustainability, economic development sustainability, social well-being sustainability, and scientific and technological innovation sustainability these four dimensions, this paper proposed model contains 19 evaluation indicators, of which 11 are inputs and 8 are outputs. This model can overcome the problems of multiple solutions and the instabilities of the average cross-efficiency model by relaxing the average hypothesis of the general cross-efficiency model, thereby reducing the distance between the weighted input and the weighted output of the regional sustainable development system assessment. Taking the evaluation of the sustainable development efficiency of 31 provinces and regions in China as an example, the results showed that the evaluation function of the comprehensive coordination and cross-efficiency evaluation model constructed in this paper has potential in measuring regional sustainable development system.

Distinct Chromatin Accessibility Changes, Aberrant Transcription Factor Networks Combined with Novel Oncogenic Enhancers Characterise Myeloma-Initiating Genetic Events

In multiple myeloma (MM), a malignancy of the bone marrow plasma cells (BMPC), hyperdiploidy (HY) and oncogene over-expression via chromosomal translocation [including CCND1- t(11;14), MAF- t(14;16), MMSET-t(4;14)] are the primary myeloma initiating events (MIE) that drive distinct transcriptional programs. These are further shaped by secondary SNV and CNV events. This genetic heterogeneity converges, in most cases, to a functionally dichotomous state of CCND1 or CCND2 overexpression. The molecular mechanisms underlying each of the distinct myelomagenic transcriptomes and the CCND1 vs CCND2 dichotomy have not been defined. To address these questions, we obtained highly purified BMPC from 3 healthy donors and 30 MM patients (HY: 15; CCND1: 4; MMSET: 5; MAF: 2; other: 4), either at diagnosis or relapse, and mapped their chromatin accessibility and transcriptome profiles by ATAC-seq and RNA-seq, respectively. In total, we obtained ~300K regions with accessible chromatin in either MM or normal PC. Overall chromatin accessibility increased in myeloma compared to normal PC, particularly in MAF- and MMSET-translocated subtypes. Analysis of combined ATAC-seq/RNA-seq by Multi-Omics Factor Analysis (MOFA) resulted in a clearer samples distinction than either ATAC-seq or RNA-seq alone, with altered chromatin accessibility accounting for more of the variance than expression. Of the top five identified factors, the top two (one transcriptome driven, one accessibility driven) distinguished normal from MM samples, whilst two more separated MMSET, MAF and CCND1 subgroups. Ninety seven, 157, 256 and 348 overexpressed genes in the CCND1, HY, MMSET and MAF subgroups, respectively, were predicted to be regulated by differentially accessible enhancers. Twenty percent (165/858) of these genes were overexpressed in &gt;1 subgroup suggesting a process of chromatin accessibility-based convergence evolution. Enrichment analysis suggested direct or indirect involvement of Polycomb and chromatin remodellers; significant enrichment was also found for genes involved in neurogenesis. ATAC-seq footprinting predicted binding sites for 250 expressed transcription factors (TFs), 116 of which displayed higher binding frequency in myeloma than in normal PC and included both known (e.g., XBP1, RELA, IRF4, PRDM1) and potentially novel regulators of myeloma biology (e.g., CXXC1 and NFE2L1). The remaining 134 TF were predicted to be present in at least one MM subgroup, but absent in normal PC. Amongst them, as expected, MAF was active in the MMSET- and more so in the MAF-translocated subgroups. DepMap database analysis suggested myeloma cell dependency on 181/250 TF (CRISPR/Cas9 CERES score &lt; -0.1 in &gt;3/14 MMCL analysed). In dissecting the regulatory basis of CCND2 vs CCND1 dichotomy, one MOFA factor completely separated MAF from CCND1 samples, placing extreme opposite weights on the expression of CCND2 and CCND1 respectively. Interestingly, the same factor identified open-chromatin clusters upstream of CCND2 and linked them to its over-expression. These clusters were also open in the MMSET group and in CCND2-expressing HY samples. Conversely, no accessibility was detected in the CCND1 group, the CCND1-expressing HY samples or in normal PCs. Further, super-enhancer calling using the H3K27ac histone mark in MAF-translocated JJN3 cells identified the region of interest as a bona fide super-enhancer. Chromatin long range interactions, as assessed by Capture-HiC, demonstrated high frequency interactions of the CCND2 promoter with the constituent elements of the putative super-enhancer. Experimental validation using a CRISPR/Cas9i system confirmed the functional role of all 4 super-enhancer constituents tested in the regulation of CCND2 expression, while TF footprinting predicted MAF binding to the super-enhancer in MAF-translocated PC. In conclusion, we show that distinct oncogenic transcriptomes in MM are underpinned by extensive chromatin changes, accompanied by TF activity 're-wiring' that does not necessarily require transcriptional deregulation of the TF themselves. We identify novel, non-oncogene TF dependencies that suggest therapeutic opportunities in MM and we discover and characterise the critical super-enhancer that drives overexpression of the CCND2 oncogene in MM. Disclosures Auner: Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy; Karyopharm: Consultancy. Hatjiharissi:Janssen: Honoraria. Caputo:GSK: Research Funding. Karadimitris:GSK: Research Funding.

Performance evaluation of regression splines for propensity score adjustment in post-market safety analysis with multiple treatments

ABSTRACTObservational studies provide a core resource in assessing post-market drug safety and effectiveness. Propensity scores are a predominant method for confounding adjustment to achieve unbiased estimation of average treatment effects in observational data. However, the use of propensity score methods has been limited to comparing two treatment groups, while medical situations frequently present with multiple treatment options. Inverse probability of treatment weighting (IPTW) is a popular propensity score adjustment method, but its performance degrades with decreased positivity leading to extreme weights, a problem that can be amplified with multiple treatment groups. Meanwhile, regression on a spline of the propensity score has shown favorable performance compared to other propensity score methods in recent studies involving two treatments. This project utilizes a simulation study to compare IPTW and propensity score splines as adjustment methods in a three-treatment setting. We test a variety of spline methods, including natural cubic splines with varying numbers of interior knots, and thin-plate regression splines. We vary several parameters across simulations, including the degree of propensity score overlap among treatment groups, treatment prevalence, outcome prevalence, and true marginal relative risk. We assess methods based on their bias, root mean squared error, and coverage of the true marginal relative risk across simulations. We find that all methods perform similarly well when there is good propensity score distribution overlap. However, with even moderate decrease in overlap or low outcome prevalence, IPTW produces more biased estimates and higher variance than propensity score splines. Low treatment prevalence or unequal treatment prevalences across groups also worsens IPTW performance. Overall, a natural cubic spline with a relatively small number of interior knots provides good performance across a range of simulations.

Propensity Score Weighting Using Overlap Weights: A New Method Applied to Regorafenib Clinical Data and a Cost-Effectiveness Analysis

BackgroundIn situations of markedly different population characteristics and weak population overlap, inverse propensity score (PS) weights suffer from extreme values. The new propensity score weighting method using overlap weights (PSOW) overcomes this limitation by estimating the overlap population at the point of highest mutual overlap, thus may be preferred to other balancing methods (trimming, target, or inverse weights) in some situations. ObjectivesTo evaluate the performance of PSOW with regorafenib effectiveness data from previously treated patients with metastatic colorectal cancer based on the Czech national registry data (regorafenib) and a global phase 3 randomized clinical trial (RCT) (placebo). The second goal was to assess the cost-effectiveness of regorafenib versus placebo. MethodsIndividual data on progression-free survival (PFS)/overall survival (OS) were balanced via PSOW for age, sex, Eastern Cooperative Oncology Group performance status, number of treatment lines, metastatic colorectal cancer location, KRAS mutation, and time from metastases estimated using logistic regression. The weighted Kaplan-Meier PFS/OS curves were used in a 3-state partitioned survival model. The R code is provided. ResultsIn comparison with target or inverse PS weights, PSOW showed remarkable performance measured by effective sample size and PS weight distribution or extreme weights despite the weak overlap between the registry and RCT. In the registry or RCT cohort, regorafenib provided better survival compared with the RCT. The new PSOW hazard ratio for OS was 0.53 (RCT: 0.79), which is conservative compared with inverse or target weights with a hazard ratio of 0.44 and 0.27, respectively. ConclusionThis is the first use of PSOW for clinical data and cost-effectiveness analysis. It is promising in cases of weak or small population overlap and makes pharmacoeconomic modeling, in such cases, feasible.

Sparse and robust mean–variance portfolio optimization problems

Mean–variance portfolios have been criticized because of unsatisfying out-of-sample performance and the presence of extreme and unstable asset weights. The bad performance is caused by estimation errors in inputs parameters, that is the covariance matrix and the expected return vector, especially the expected return vector. This topic has attracted wide attention. In this paper, we aim to find better portfolio optimization model to reduce the undesired impact of parameter uncertainty and estimation errors of mean–variance portfolio model. Firstly, we introduce a sparse mean–variance portfolio model, and give some insight about sparsity. Secondly, we propose two sparse and robust portfolio models by using objective function regularization and robust optimization. Finally, three empirical studies are proposed with real market data.