Survival Models Research Articles

Non-proportional hazards model with a PVF frailty term: application with a melanoma dataset

Survival data analysis often uses the Cox proportional hazards (PH) model. This model is widely applied due to its straightforward interpretation of the hazard ratio under the assumption that the hazard rates for two subjects remain constant over time. However, in several randomized clinical trials with long-term survival data comparing two new treatments, it is frequently observed that Kaplan-Meier plots exhibit crossing survival curves. This violation of the PH assumption of the Cox PH model can not be applied to evaluate the treatment's effect on survival. This paper introduces a novel long-term survival model with non-PH that incorporates a frailty term into the hazard function. This model allows us to examine the effect of prognostic factors on survival and quantify the degree of unobservable heterogeneity. The model parameters are estimated using the maximum likelihood estimation procedure, and we evaluate the performance of the proposed models through simulation studies. Additionally, we demonstrate the applicability of our approach by fitting the models to a real skin cancer dataset.

A ferroptosis-related signature predicts the clinical diagnosis and prognosis, and associates with the immune microenvironment of lung cancer

Targeting ferroptosis-related pathway is a potential strategy for treatment of lung cancer (LC). Consequently, exploration of ferroptosis-related markers is important for treating LC. We collected LC clinical data and mRNA expression profiles from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained through FerrDB database. Expression analysis was performed to obtain differentially expressed FRGs. Diagnostic and prognostic models were constructed based on FRGs by LASSO regression, univariate, and multivariate Cox regression analysis, respectively. External verification cohorts GSE72094 and GSE157011 were used for validation. The interrelationship between prognostic risk scores based on FRGs and the tumor immune microenvironment was analyzed. Immunocytochemistry, Western blotting, and RT-qPCR detected the FRGs level. Eighteen FRGs were used for diagnostic models, 8 FRGs were used for prognostic models. The diagnostic model distinguished well between LC and normal samples in training and validation cohorts of TCGA. The prognostic models for TCGA, GSE72094, and GSE157011 cohorts significantly confirmed lower overall survival (OS) in high-risk group, which demonstrated excellent predictive properties of the survival model. Multivariate Cox regression analysis further confirmed risk score was an independent risk factor related with OS. Immunoassays revealed that in high-risk group, a significantly higher proportion of Macrophages_M0, Neutrophils, resting Natural killer cells and activated Mast cells and the level of B7H3, CD112, CD155, B7H5, and ICOSL were increased. In conclusion, diagnostic and prognostic models provided superior diagnostic and predictive power for LC and revealed a potential link between ferroptosis and TIME.

Analysis of survival rates and evaluation of prognostic factors in patients with lung metastases from renal cell carcinoma

In patients with lung metastases from renal cell cancer (RCC), it is necessary to search for new prognostic factors influencing survival rates. Aim: To analyze survival rates and identify prognostic factors in patients with lung metastases from RCC. Material and methods. We retrospectively analyzed the data from 655 patients with lung metastases from RCC, who were treated at Moscow city oncology Hospital No. 62 (Moscow) and city clinical oncology center (Saint Petersburg) from 2006 to 2022. Of these patients, 241 (36.8 %) were classified into the intermediate prognosis group, and 278 (42.2 %) into the unfavorable prognosis group. The study investigated clinical and morphologic prognostic factors influencing survival rates in patients with lung metastases from RCC. Statistical analysis was performed using Statistica 10.0 software packages (StatSoft, USA) by constructing Kaplan-Meier curves and survival tables, building a mathematical model of survival. Results. The 3- and 5-year OS rates in patients with lung metastases from RCC (N=655) were 48 % [95 % ci 45–53 %] and 27 % [95 % ci 23–31 %], respectively, with a median OS of 34.9 months [95 % ci 30.4–37.4]. in univariate analysis, ECOG status (p<0.001), histological subtype (p<0.001), Fuhrman grade of tumor differentiation (p<0.001), type and number of metastases (p<0.001), metastases to the bones and liver (p<0.001), lymph nodes (p=0.001), prognosis according to IMDC(p<0.001), nephrectomy and metastasectomy (p<0.001) had a negative impact on OS in patients with lung metastases from RCC. In multivariate analysis, ECOG status 3.66 (2.10–6.39, p<0.001), histological subtype 1.49 (1.10–2.01, p=0.009), grade of tumor differentiation according to Fuhrman 1.54 (1.13–2.09, p=0.006), number of metastases 3.63 (1.44–9.16, p=0.006), prognosis according to IMDC2.27 (1.63–3.17, p<0.001), and nephrectomy 1.87 (1.29–2.70, p=0.001) and metastasectomy 0.69 (0.53–0.88, p=0.003) were additional factors influencing OS rates in patients with lung metastases from RCC. Conclusion. In our study, ECOG status, histologic subtype of RCC, Fuhrman grade of tumor differentiation, number of metastases, IMDC prognosis, and nephrectomy and metastasectomy were additional independent prognostic factors affecting OS in patients with lung metastases from RCC. Further studies are needed to investigate prognostic factors in patients with RCC lung metastases to improve the effectiveness of personalized treatment and survival rates.

Why do users continue to contribute to darknet Child Sexual Abuse Material forums? Examining social exchange, social capital, and social learning explanations using digital forensic artifacts

BackgroundThe darknet hosts an increasing number of hidden services dedicated to the distribution of child sexual abuse material (CSAM). Given that by contributing CSAM to the forum members subject themselves to criminal prosecution, questions regarding the motivation for members contributing to darknet CSAM forums arise. ObjectiveBuilding on insights gained from research into clearnet communities, here we examine the extent to which social incentives generated by the online CSAM community may explain members' posting behavior on darknet CSAM forums. Participants and settingWe analyze digital forensic artifacts on the online behavior of members of a darknet CSAM forum that was shut down by law enforcement agencies in July 2015. MethodsWe apply group-based trajectory modelling (GBTM), social network analysis, and mixed-effect survival models. ResultsApplying GBTM three posting trajectories can be distinguished. Social network analyses finds the reply network to be more centralized than predicted by chance. Mixed-effect survival models show positive associations between the length of members' first post and the time since members' first registration on the forum and subsequent posting. Contrarily, the number of replies received appears to mitigate subsequent posting. ConclusionsFindings show posting activity on the forum to be concentrated in a minority of forum members who show posting trajectories that are both frequent and persistent. Results further suggest persistence in posting is motivated by social identity and, to a lesser extent, differential association processes.

The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Cost-effectiveness of avelumab first-line maintenance therapy for adult patients with locally advanced or metastatic urothelial carcinoma in France.

This study evaluated the cost-effectiveness of avelumab first-line (1L) maintenance therapy plus best supportive care (BSC) versus BSC alone for adults with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed following platinum-based chemotherapy in France. A three-state partitioned survival model was developed to assess the lifetime costs and effects of avelumab plus BSC versus BSC alone. Data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) were used to inform estimates of clinical and utility values considering a 10-year time horizon and a weekly cycle length. Cost data were estimated from a collective perspective and included treatment acquisition, administration, follow-up, adverse event-related hospitalization, transport, post-progression, and end-of-life costs. Health outcomes were measured in quality-adjusted life-years (QALYs) and life-years gained. Costs and clinical outcomes were discounted at 2.5% per annum. Incremental cost-effectiveness ratios (ICERs) were used to compare cost-effectiveness and willingness to pay in France. Uncertainty was assessed using a range of sensitivity analyses. Avelumab plus BSC was associated with a gain of 2.49 QALYs and total discounted costs of €136,917; BSC alone was associated with 1.82 QALYs and €39,751. Although avelumab plus BSC was associated with increased acquisition costs compared with BSC alone, offsets of -€20,424 and -€351 were observed for post-progression and end-of-life costs, respectively. The base case analysis ICER was €145,626/QALY. Sensitivity analyses were consistent with the reference case and showed that efficacy parameters (overall survival, time to treatment discontinuation), post-progression time on immunotherapy, and post-progression costs had the largest impact on the ICER. This analysis demonstrated that avelumab plus BSC is associated with a favorable cost-effectiveness profile for patients with la/mUC who are eligible for 1L maintenance therapy in France.

Weibull parametric model for survival analysis in women with endometrial cancer using clinical and T2-weighted MRI radiomic features

BackgroundSemiparametric survival analysis such as the Cox proportional hazards (CPH) regression model is commonly employed in endometrial cancer (EC) study. Although this method does not need to know the baseline hazard function, it cannot estimate event time ratio (ETR) which measures relative increase or decrease in survival time. To estimate ETR, the Weibull parametric model needs to be applied. The objective of this study is to develop and evaluate the Weibull parametric model for EC patients’ survival analysis.MethodsTraining (n = 411) and testing (n = 80) datasets from EC patients were retrospectively collected to investigate this problem. To determine the optimal CPH model from the training dataset, a bi-level model selection with minimax concave penalty was applied to select clinical and radiomic features which were obtained from T2-weighted MRI images. After the CPH model was built, model diagnostic was carried out to evaluate the proportional hazard assumption with Schoenfeld test. Survival data were fitted into a Weibull model and hazard ratio (HR) and ETR were calculated from the model. Brier score and time-dependent area under the receiver operating characteristic curve (AUC) were compared between CPH and Weibull models. Goodness of the fit was measured with Kolmogorov-Smirnov (KS) statistic.ResultsAlthough the proportional hazard assumption holds for fitting EC survival data, the linearity of the model assumption is suspicious as there are trends in the age and cancer grade predictors. The result also showed that there was a significant relation between the EC survival data and the Weibull distribution. Finally, it showed that Weibull model has a larger AUC value than CPH model in general, and it also has smaller Brier score value for EC survival prediction using both training and testing datasets, suggesting that it is more accurate to use the Weibull model for EC survival analysis.ConclusionsThe Weibull parametric model for EC survival analysis allows simultaneous characterization of the treatment effect in terms of the hazard ratio and the event time ratio (ETR), which is likely to be better understood. This method can be extended to study progression free survival and disease specific survival.Trial registrationClinicalTrials.gov NCT03543215, https://clinicaltrials.gov/, date of registration: 30th June 2017.

Interpretable (not just posthoc-explainable) medical claims modeling for discharge placement to reduce preventable all-cause readmissions or death

We developed an inherently interpretable multilevel Bayesian framework for representing variation in regression coefficients that mimics the piecewise linearity of ReLU-activated deep neural networks. We used the framework to formulate a survival model for using medical claims to predict hospital readmission and death that focuses on discharge placement, adjusting for confounding in estimating causal local average treatment effects. We trained the model on a 5% sample of Medicare beneficiaries from 2008 and 2011, based on their 2009–2011 inpatient episodes (approximately 1.2 million), and then tested the model on 2012 episodes (approximately 400 thousand). The model scored an out-of-sample AUROC of approximately 0.75 on predicting all-cause readmissions—defined using official Centers for Medicare and Medicaid Services (CMS) methodology—or death within 30-days of discharge, being competitive against XGBoost and a Bayesian deep neural network, demonstrating that one need-not sacrifice interpretability for accuracy. Crucially, as a regression model, it provides what blackboxes cannot—its exact gold-standard global interpretation, explicitly defining how the model performs its internal “reasoning” for mapping the input data features to predictions. In doing so, we identify relative risk factors and quantify the effect of discharge placement. We also show that the posthoc explainer SHAP provides explanations that are inconsistent with the ground truth model reasoning that our model readily admits.

Computation of the Mann–Whitney Effect under Parametric Survival Copula Models

The Mann–Whitney effect is a measure for comparing survival distributions between two groups. The Mann–Whitney effect is interpreted as the probability that a randomly selected subject in a group survives longer than a randomly selected subject in the other group. Under the independence assumption of two groups, the Mann–Whitney effect can be expressed as the traditional integral formula of survival functions. However, when the survival times in two groups are not independent of each other, the traditional formula of the Mann–Whitney effect has to be modified. In this article, we propose a copula-based approach to compute the Mann–Whitney effect with parametric survival models under dependence of two groups, which may arise in the potential outcome framework. In addition, we develop a Shiny web app that can implement the proposed method via simple commands . Through a simulation study, we show the correctness of the proposed calculator. We apply the proposed methods to two real datasets.

Analysis of Copula Frailty defective models in presence of Cure Fraction

Introduction: Analyzing long term survivors such as diabetic patients can't be done using the usual survival models. One approach to analyze it is using defective distribution that doesn't force a pre-assumption of cure fraction to the model. To study more than one random variable interacting together, multivariate distributions may be used. However, most of multivariate distributions have complicated forms, which make the computations difficult. Besides, it may be hard to find a multivariate distribution that fits the data properly, especially in health care field. To get over this problem, one can use copula approach. In literature, to the best of our knowledge, only one paper handled copula defective models and didn't consider the effect of covariates. In this paper, we take into consideration not only existed covariates but also unobserved ones by including frailty term. Methods: Two new models are introduced. The first model, used Gumbel copula to take the dependence into consideration together with the observed covariates. The second one take into consideration not only the dependence but also the unobserved covariates by integrating frailty term in to the model. Results: A diabetic retinopathy data is analyzed. The two models indicated the existence of long-term survivals through negative parameters without the need of pre-assuming the existence of it. Including frailty term to the model helped in capturing more dependence between the variables. We compared the results using goodness of fit methods, and the results suggested that the model with frailty term is the best to be used. Conclusion: The two introduced models correctly detected the existence of cure fraction with less estimated parameters than that in mixture cure fraction models. Also, it has the advantage of not pre-assuming the existence of cure fraction to the model. comparing both models, the model with frailty term fitted the data better.

Evaluating the cost-effectiveness of voclosporin for the treatment of lupus nephritis in the United States.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus; up to 30% of patients with LN will develop end-stage kidney disease (ESKD). One of the main treatment goals for LN is preservation of kidney function, with early decreases in proteinuria associated with improved long-term outcomes. Voclosporin, a second-generation calcineurin inhibitor, was approved in the United States in 2021 for the treatment of active LN combined with background immunosuppression. The AURORA 1 study found that the use of voclosporin with low doses of mycophenolate mofetil and glucocorticoids yielded significant reductions in proteinuria. The AURORA 2 study showed long-term efficacy and safety of voclosporin over a 3-year period with kidney function preservation. The Institute for Clinical and Economic Review (ICER) is a nonprofit organization that evaluates medical evidence to help improve patient outcomes and control costs. In 2021, ICER published an economic model to estimate the impact and cost-effectiveness of LN therapies. From a US health care perspective, voclosporin was cost-effective at $149,260 per quality-adjusted life-year (QALY) and $131,528 per equal value of life-years gained (evLYG). At the time of the LN cost-effectiveness model (CEM) development, voclosporin was not yet approved in the United States and the cost of treating patients with LN with ESKD was not captured in the literature. To evaluate the cost-effectiveness of voclosporin given the emergence of new data. The LN CEM uses a short-term trial-based Markov model and long-term extrapolation using partitioned survival modeling data assuming adults with LN start with active disease, transitioning to complete or partial renal response, kidney failure, or death. In the current analysis, clinical data for voclosporin, duration of voclosporin treatment for nonresponders, and drug costs reflecting the 2023 price of voclosporin were updated. Additionally, health care payer costs of disease management were incorporated based on real-world claims data on the costs of treating patients with LN. Using the LN CEM with inputs reflecting the latest and most relevant evidence, the incremental cost of voclosporin per QALY was $88,076 and per evLYG was $77,643. For a subpopulation of Black, Hispanic, and Latino patients, the incremental cost of voclosporin per QALY was $77,435 and per evLYG was $67,828. Following the inclusion of updated data in the cost-effectiveness analysis, voclosporin remains a cost-effective therapy for the treatment of active LN including in a Black, Hispanic, and Latino subpopulation, substantially below the ICER willingness-to-pay threshold of $150,000/QALY.

Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Prostate cancer diagnosis rates among insured men with and without HIV in South Africa: a cohort study.

Several studies have found lower prostate cancer diagnosis rates among men with HIV (MWH) than men without HIV, but reasons for this finding remain unclear. We used claims data from a South African private medical insurance scheme (07/2017-07/2020) to assess prostate cancer diagnosis rates among men aged ≥18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model), and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen (PSA) testing, and prostate biopsies (fully adjusted model). We included 288 194 men, of whom 20 074 (7%) were living with HIV. Prostate cancer was diagnosed in 1 614 men without HIV (median age at diagnosis: 67 years) and in 82 MWH (median age at diagnosis: 60 years). In the unadjusted analysis, prostate cancer diagnosis rates were 35% lower among MWH than men without HIV (HR 0.65, 95% confidence interval [CI] 0.52-0-82). However, this association was no longer evident in the confounder-adjusted model (HR 1.03, 95% CI 0.82-1.30) or in the fully adjusted model (HR 1.14, 95% CI 0.91-1.44). When accounting for potential confounders and mediators, our analysis found no evidence of lower prostate cancer diagnosis rates among men with HIV than men without HIV in South Africa. Our results do not support the hypothesis that HIV decreases the risk of prostate cancer.

Improved nonparametric survival prediction using CoxPH, Random Survival Forest & DeepHit Neural Network

In recent times, time-to-event data such as time to failure or death is routinely collected alongside high-throughput covariates. These high-dimensional bioinformatics data often challenge classical survival models, which are either infeasible to fit or produce low prediction accuracy due to overfitting. To address this issue, the focus has shifted towards introducing a novel approaches for feature selection and survival prediction. In this article, we propose a new hybrid feature selection approach that handles high-dimensional bioinformatics datasets for improved survival prediction. This study explores the efficacy of four distinct variable selection techniques: LASSO, RSF-vs, SCAD, and CoxBoost, in the context of non-parametric biomedical survival prediction. Leveraging these methods, we conducted comprehensive variable selection processes. Subsequently, survival analysis models—specifically CoxPH, RSF, and DeepHit NN—were employed to construct predictive models based on the selected variables. Furthermore, we introduce a novel approach wherein only variables consistently selected by a majority of the aforementioned feature selection techniques are considered. This innovative strategy, referred to as the proposed method, aims to enhance the reliability and robustness of variable selection, subsequently improving the predictive performance of the survival analysis models. To evaluate the effectiveness of the proposed method, we compare the performance of the proposed approach with the existing LASSO, RSF-vs, SCAD, and CoxBoost techniques using various performance metrics including integrated brier score (IBS), concordance index (C-Index) and integrated absolute error (IAE) for numerous high-dimensional survival datasets. The real data applications reveal that the proposed method outperforms the competing methods in terms of survival prediction accuracy.

Cost-effectiveness analysis of mosunetuzumab for treatment of relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in the United States

Aims Mosunetuzumab has received accelerated approval by the US Food and Drug Administration for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of systemic therapy. We evaluated the cost-effectiveness of mosunetuzumab for the treatment of R/R FL from a US private payer perspective. Materials and Methods A partitioned survival model simulated lifetime costs and outcomes of mosunetuzumab against seven comparators: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), tazemetostat (taz, EZH2 wild-type only), rituximab plus lenalidomide (R-Len) or bendamustine (R-Benda), obinutuzumab plus bendamustine (O-Benda), and a retrospective real-world cohort (RW) based on current patterns of care derived from US electronic health records (Flatiron Health). Efficacy data for mosunetuzumab were from the pivotal Phase II GO29781 trial (NCT02500407). Relative treatment efficacy was estimated from indirect treatment comparisons (ITCs). Costs included were related to treatment, adverse events, routine care, and terminal care. Except for drug costs (March 2023), all costs were inflated to 2022 US dollars. Costs and quality-adjusted life-years (QALYs) were used to calculate incremental cost-effectiveness ratios (ICERs). Net monetary benefit (NMB) was calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. Results Mosunetuzumab dominated taz, tisa-cel, and axi-cel with greater QALYs and lower costs. Mosunetuzumab was projected to be cost-effective against R-Benda, O-Benda, and RW with ICERs of $78,607, $42,731, and $21,434, respectively. Mosunetuzumab incurred lower costs but lower QALYs vs. R-Len. NMBs showed that mosunetuzumab was cost-effective against comparators except R-Len. Limitations Without head-to-head comparative data, the model had to rely on ITCs, some of which were affected by residual bias. Model inputs were obtained from multiple sources. Extensive sensitivity analyses assessed the importance of these uncertainties. Conclusion Mosunetuzumab is estimated to be cost-effective compared with approved regimens except R-Len for the treatment of adults with R/R FL.

Analysis of the virulence and genetic differences of carbapenem-resistant Acinetobacter baumannii epidemic clones

Objective: To evaluate the virulence levels of carbapenem-resistant Acinetobacter baumannii ST191, ST195, and ST208, and to analyze the differences in virulence factors among these epidemic clones. Methods: The study involved the genomic sequencing of 233 Acinetobacter baumannii strains that were isolated from the Fifth Medical Center of the Chinese People's Liberation Army General Hospital (North Hospital) between 2011 and 2019. The genomic data was cross-referenced with the Virulence Factor Database (VFDB) to examine the presence of virulence genes in the strains. Furthermore, a Galleria mellonella infection survival model was used to evaluate the virulence levels of the strains, and the association between virulence levels and virulence genes was analyzed. Results: The study included 38 strains of the ST191 clone, 104 strains of the ST195 clone, and 91 strains of the ST208 clone. In the Galleria mellonella infection survival experiment, the average mortality rate for ST191 was 23.0%, with 3 (7.9%) highly virulent strains. For ST195, the average mortality rate was 53.0%, with 34 (32.7%) highly virulent strains. For ST208, the average mortality rate was 47.0%, with 20 (21.9%) highly virulent strains. There was a significant statistical difference in mortality rates between ST191 and ST195 (χ2=13.9, P<0.001) as well as between ST191 and ST208 (χ2=15.2, P<0.001). A comparison of the strains with the VFDB revealed significant differences in the virulence genes carried by the clones. Specifically, the type Ⅵ secretion system-related genes (clpV/tssH, hcp/tssD, tagX, tssA, tssB, tssC, tssE, tssF, tssG, tssK, ssL, tssM) and the sugar transferase gene ACICU_RS00475 were found to be universally absent in ST191 strains (0%) while being prevalent in ST195 (100.0%) and ST208 (>82.0%) strains. Statistical analysis revealed an association between the mortality rate of the clones and the presence of virulence genes(clpV/tssH P<0.001, hcp/tssD P=0.001, tagX P<0.001, tssA P<0.001, tssB P=0.001, tssC P=0.001, tssE P=0.001, tssF P=0.001, tssG P<0.001, tssK P<0.001, tssL P<0.001, tssM P=0.001, ACICU_RS00475 P=0.001). Conclusion: Among the carbapenem-resistant epidemic clones of Acinetobacter baumannii, the ST191 clone shows lower mortality rates in Galleria mellonella, possibly because of the lack of type Ⅵ secretion system and sugar transferase genes.

284 Relationship between sow caliper measurements with sow reproductive performance and longevity in the herd

Abstract Ideal conditioned sows are desired because they maximize herd performance, improve female well-being, and optimize financial outcomes. Sow productivity has increased, and body composition of females has changed, with sows being leaner and having less adipose tissue compared with their predecessors. Our objective was to determine the relationship between sow caliper measurements with sow reproductive performance and longevity in the herd. Data collected in four different production systems located in the US and Brazil were used, with 3,083, 356, 7,456, and 26,773 individual PIC Camborough observations represented within each of these databases. Caliper measurements were collected at due to farrow and weaned sows and were recorded in units, standardized to an ideal range of 12 to 15 units. Caliper change in lactation was determined as the caliper units at weaning minus the caliper units pre-farrowing. Response variables included proportion of born alive and stillborn piglets, lactation feed intake, as well as removal and mortality risk for all causes, or specifically for reproductive and pelvic organ prolapse (POP) causes. Data were analyzed using generalized linear mixed models, hazard ratio analysis, and survival models with the lmer, glmer, and surv functions of R. Sow served as the experimental unit. Caliper measurements at farrowing had curvilinear associations (P &amp;lt; 0.05) with percentage born alive piglets and percentage stillborn piglets. Increasing caliper units at farrowing resulted in linear reduction (P &amp;lt; 0.05) in lactation average daily feed intake and in linear increase (P &amp;lt; 0.05) in caliper losses during lactation. Sows losing 1 to 2, 3 to 4, or 5 and greater caliper units in lactation had 1.5, 1.8, and 2.4 times, respectively, greater risk (P &amp;lt; 0.05) of being removed from the herd in the next cycle compared with sows that gained 0 or more units. Reduced caliper units in due-to-farrow sows resulted in reduced probability (P &amp;lt; 0.05) of survival in the next cycle considering prolapse removal reasons. Sows with due to farrow caliper units of 12 to 15 had 1 to 1.6 times (95% Odd Ratio Confidence Interval), 9 to 11 had 1.2 to 2.1 times, and less than 9 caliper units 3.1 to 3.2 times greater risk of death or being removed from the herd due to POP compared with those with &amp;gt;15 units. Reduced caliper units in due-to-farrow sows resulted in reduced probability of survival in the next cycle considering all removal and mortality causes. Specifically, sows with less than 9 caliper units at farrowing had 2.0 times greater risk (P &amp;lt; 0.05) of removal and 4.4 times greater risk (P &amp;lt; 0.05) of mortality compared with sows with over 15 caliper units. In summary, both under and over-conditioned sows have reduced productivity. Underconditioned sows are at greater risk for mortality and for POP related removal.

Clinical and economic implications of using daratumubab with lenalidomide in the 1st and 2nd lines of therapy for multiple myeloma patients

Objective: to assess clinical and economic implications of adding daratumumab (Dara) to the “lenalidomide + dexamethasone” (Rd) treatment program in early lines of therapy for patients with multiple myeloma (MM) ineligible for high-dose chemotherapy (HDCT) with subsequent autologous hematopoietic stem cell transplantation (autoHPSCT).Material and methods. Partitioned survival model was developed to compare overall survival in the treatment programs of MM patients in the 1st to 3rd lines of therapy. The following treatment options were included in the analysis: 1st line – Dara+Rd; 2nd line – “carfilzomib + lenalidomide” (K+Rd) or “ixazomib + lenalidomide” (Ixa+Rd) triplets; 3rd line – pomalidomide (Pom+dex) and Rd+(Dara+Rd)+(Pom+dex) versus Rd+(K/Ixa+Rd)+(Pom+dex/Dara). Probabilities of transition between health states (progression-free, progressed disease, and death) were based on published clinical data. Lifetime direct healthcare costs and incremental cost-effectiveness ratios (ICERs) per 1 life year gained were calculated from a Russian health care perspective. The indicator of the difference in costs between current and expected practice was used in budget impact analysis.Results. Dara+Rd combination increased life expectancy by 1.04 years (+16.05%) and 0.95 years (+14.57%) per patient, and in the target population (n=955) by 995.48 and 903.40 years for (Dara+Rd)+(K+Rd)+(Pom+dex) and (Dara+Rd)+(Ixa+Rd)+(Pom+dex) treatment programs, respectively, compared to Rd use in the 1st line. The ICER per 1 life year gained for Dara+Rd in 1st line therapy was 8.95 mln rubles for (Dara+Rd)+(K+Rd)+(Pom+dex) and 8.41 mln rubles for (Dara+Rd)+(Ixa+Rd)+(Pom+dex). It's lower than the median ICER of 13.64 million per 1 life year gained for antitumor drugs used to treat cancer of lymphatic and hematopoietic tissues (reference ICER). Dara+Rd triplet is used in 2nd line therapy after Rd, the number of life years gained in the target population due to greater efficacy is higher by 291.50 years compared with K+Rd and by 203.93 years compared with Ixa+Rd. The ICER per 1 life year gained for Dara+Rd is also lower than the ICER reference value: 9.25 mln rubles versus 13.64 mln rubles. The budget impact analysis showed that using Dara in early stages of MM therapy does not increase drug provision costs in the target population.Conclusion. The obtained results allowed to conclude that it is economically feasible to add Dara to the 1st and 2nd lines of therapy in lenalidomide treatment programs for MM patients who are not candidates for HDCT with autoHPSCT.

Statistical design and analysis of controlled human malaria infection trials

BackgroundMalaria is a potentially life-threatening disease caused by Plasmodium protozoa transmitted by infected Anopheles mosquitoes. Controlled human malaria infection (CHMI) trials are used to assess the efficacy of interventions for malaria elimination. The operating characteristics of statistical methods for assessing the ability of interventions to protect individuals from malaria is uncertain in small CHMI studies. This paper presents simulation studies comparing the performance of a variety of statistical methods for assessing efficacy of intervention in CHMI trials.MethodsTwo types of CHMI designs were investigated: the commonly used single high-dose design (SHD) and the repeated low-dose design (RLD), motivated by simian immunodeficiency virus (SIV) challenge studies. In the context of SHD, the primary efficacy endpoint is typically time to infection. Using a continuous time survival model, five statistical tests for assessing the extent to which an intervention confers partial or full protection under single dose CHMI designs were evaluated. For RLD, the primary efficacy endpoint is typically the binary infection status after a specific number of challenges. A discrete time survival model was used to study the characteristics of RLD versus SHD challenge studies.ResultsIn a SHD study with the continuous time survival model, log-rank test and t-test are the most powerful and provide more interpretable results than Wilcoxon rank-sum tests and Lachenbruch tests, while the likelihood ratio test is uniformly most powerful but requires knowledge of the underlying probability model. In the discrete time survival model setting, SHDs are more powerful for assessing the efficacy of an intervention to prevent infection than RLDs. However, additional information can be inferred from RLD challenge designs, particularly using a likelihood ratio test.ConclusionsDifferent statistical methods can be used to analyze controlled human malaria infection (CHMI) experiments, and the choice of method depends on the specific characteristics of the experiment, such as the sample size allocation between the control and intervention groups, and the nature of the intervention. The simulation results provide guidance for the trade off in statistical power when choosing between different statistical methods and study designs.

ESTIMATING THE RISK OF POSTOPERATIVE PERIPROSTHETIC FEMORAL FRACTURES AFTER TOTAL HIP ARTHROPLASTY ASSOCIATED WITH COMMONLY USED IMPLANTS: AN ANALYSIS OF NATIONAL HEALTH DATA FROM ENGLAND

Current estimates of periprosthetic fracture risk associated with femoral implants is mostly limited to revision only estimates and does not accurately represent stem performance. The aim of this study was to estimate the risk of surgically treated post-operative periprosthetic femoral fracture (POPFF) more accurately associated with frequently used femoral implants used for total hip arthroplasty (THA).A cohort study of patients who underwent primary THA in England between January 1, 2004, and December 31, 2020. Periprosthetic fractures were identified from prospectively collected revision records and national procedure coding records. Survival modelling was used to estimate POPFF incidence rates, adjusting for potential confounders. Subgroup analyses were performed for patients over 70 years, with non-osteoarthritic indications, and neck of femur fracture.POPFF occurred in 0.6% (5100/809,832) of cases during a median (IQR) follow up of 6.5 (3.9 to 9.6) years. The majority of POPFF were treated with fixation after implantation of a cemented stem. Adjusted patient time incidence rates (PTIR) for POPFF varied by stem design, regardless of cement fixation. Cemented composite beam stems (CB stems) demonstrated the lowest risk of POPFF. Collared cementless stems had an equivalent or lower rate of POPFF versus the current gold standard polished taper slip cemented stem.POPFF account for a quarter of all revisions following primary THA. Cemented CB stems are associated with the lowest POPFF risk. Stem design is strongly associated with POPFF risk, regardless of the presence of cement. Surgeons, policymakers, and patients should consider these findings when recommending femoral implants in those most at risk of POPFF.