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Xu, Ronghui. "Proportional hazards mixed models." Advances in Methodology and Statistics 1, no. 1 (January 1, 2004): 205–12. http://dx.doi.org/10.51936/lmzi2020.
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We describe our recent work on mixed effects models for right-censored data. Vaida and Xu (2000) provided a general framework for handling random effects in proportional hazards (PH) regression, in a way similar to the linear, non-linear and generalized linear mixed effects models that allow random effects of arbitrary covariates. This general framework includes the frailty models as a special case. Maximum likelihood estimates of the regression parameters, the variance components and the baseline hazard, and empirical Bayes estimates of the random effects can be obtained via an MCEM algoritm. Variances of the parameter estimates are approximated using Louis' formula. We show interesting applications of the PH mixed effects model (PHMM) to a US Vietnam Era Twin Registry study on alcohol abuse, with the primary goal of identifying genetic contributions to such events. The twin pairs in the registry consist of monozygotic and dizygotic twins. After model fitting and for interpretation purposes, the proportional hazards formulation is converted to a linear transformation model before the results on genetic contributions are reported. The model also allows examination of gene and covariate interactions, as well as the modelling of multivariate outcomes (comorbidities).
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Asadi, Majid, Nader Ebrahimi, and Ehsan S. Soofi. "Connections of Gini, Fisher, and Shannon by Bayes risk under proportional hazards." Journal of Applied Probability 54, no. 4 (November 30, 2017): 1027–50. http://dx.doi.org/10.1017/jpr.2017.51.
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Abstract The proportional hazards (PH) model and its associated distributions provide suitable media for exploring connections between the Gini coefficient, Fisher information, and Shannon entropy. The connecting threads are Bayes risks of the mean excess of a random variable with the PH distribution and Bayes risks of the Fisher information of the equilibrium distribution of the PH model. Under various priors, these Bayes risks are generalized entropy functionals of the survival functions of the baseline and PH models and the expected asymptotic age of the renewal process with the PH renewal time distribution. Bounds for a Bayes risk of the mean excess and the Gini's coefficient are given. The Shannon entropy integral of the equilibrium distribution of the PH model is represented in derivative forms. Several examples illustrate implementation of the results and provide insights for potential applications.
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Farooq, Fabiha Binte, and Md Jamil Hasan Karami. "Model Selection Strategy for Cox Proportional Hazards Model." Dhaka University Journal of Science 67, no. 2 (July 30, 2019): 111–16. http://dx.doi.org/10.3329/dujs.v67i2.54582.
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Often in survival regression modelling, not all predictors are relevant to the outcome variable. Discarding such irrelevant variables is very crucial in model selection. In this research, under Cox Proportional Hazards (PH) model we study different model selection criteria including Stepwise selection, Least Absolute Shrinkage and Selection Operator (LASSO), Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC) and the extended versions of AIC and BIC to the Cox model. The simulation study shows that varying censoring proportions and correlation coefficients among the covariates have great impact on the performances of the criteria to identify a true model. In the presence of high correlation among the covariates, the success rate for identifying the true model is higher for LASSO compared to other criteria. The extended version of BIC always shows better result than the traditional BIC. We have also applied these techniques to real world data.
Dhaka Univ. J. Sci. 67(2): 111-116, 2019 (July)
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ZHANG, HAO, and ELSAYED A. ELSAYED. "NONPARAMETRIC ACCELERATED LIFE TESTING BASED ON PROPORTIONAL ODDS MODEL." International Journal of Reliability, Quality and Safety Engineering 13, no. 04 (August 2006): 365–78. http://dx.doi.org/10.1142/s0218539306002318.
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Accelerated life testing (ALT) is used to obtain failure time data in short duration under high stress levels in order to predict product life and performance under design conditions. The proportional hazards (PH) model, a widely used reliability prediction model, assumes constant ratio between the failure rate at high stress levels and the failure rate at the normal operating conditions. However, this assumption might be violated under some conditions and the prediction of the failure rate at normal conditions becomes inaccurate. We investigate the proportional odds (PO) model, which assumes that the odds ratio under different stress levels is constant, for accelerating life testing. In this research, we propose a nonparametric ALT approach based on the proportional odds model to predict reliability at normal operating conditions. We estimate the parameters of the proposed ALT model using the maximum likelihood estimation method. To verify the new approach, we fit the PO model with simulated failure time datasets and experimental failure data and compare its performance with the PH model. The results show that the new approach based on the PO model is a viable complement to the PH model in estimating reliability of products possessing property of converging hazard rate functions.
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Equeter, Lucas, François Ducobu, Edouard Rivière-Lorphèvre, Roger Serra, and Pierre Dehombreux. "An Analytic Approach to the Cox Proportional Hazards Model for Estimating the Lifespan of Cutting Tools." Journal of Manufacturing and Materials Processing 4, no. 1 (March 24, 2020): 27. http://dx.doi.org/10.3390/jmmp4010027.
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The machining industry raises an ever-growing concern for the significant cost of cutting tools in the production process of mechanical parts, with a focus on the replacement policy of these inserts. While an early maintenance induces lower tool return on investment, scraps and inherent costs stem from late replacement. The framework of this paper is the attempt to predict the tool inserts Mean Up Time, based solely on the value of a cutting parameter (the cutting speed in this particular turning application). More specifically, the use of the Cox Proportional Hazards (PH) Model for this prediction is demonstrated. The main contribution of this paper is the analytic approach that was conducted about the relevance on data transformation prior to using the Cox PH Model. It is shown that the logarithm of the cutting speed is analytically much more relevant in the prediction of the Mean Up Time through the Cox PH model than the raw cutting speed value. The paper also covers a numerical validation designed to show and discuss the benefits of this data transformation and the overall interest of the Cox PH model for the lifetime prognosis. This methodology, however, necessitates the knowledge of an analytical law linking the covariate to the Mean Up Time. It also shows how the necessary data for the numerical experiment was obtained through a gamma process simulating the degradation of cutting inserts. The results of this paper are expected to help manufacturers in the assessment of tool lifespan.
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Telford, Claire, Shweta Takyar, Parth Joshi, Mattias Ekman, and Nick Jones. "A network meta-analysis of fulvestrant vs alternative first-line endocrine therapies for endocrine therapy-naive postmenopausal hormone receptor-positive advanced or metastatic breast cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12545-e12545. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12545.
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e12545 Background: Fulvestrant (F) is a selective estrogen degrader for hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). This network meta-analysis examined the efficacy of F (500 mg) vs alternative endocrine therapies (ETs) for first-line treatment of ET-naïve HR+ LA/MBC. Methods: Randomized controlled trials of first-line F, tamoxifen (Tam), anastrozole (A), exemestane (E), letrozole (L), and toremifene (T) for women (≥18 years) with HR+ LA/MBC and no prior ET were identified in a systematic review of MEDLINE, EMBASE, and Cochrane databases from inception to October 2016. Conference proceedings of the American Society of Clinical Oncology, European Society of Medical Oncology, and San Antonio Breast Cancer Symposium from 2013-2016 were hand searched. Trials of targeted combination therapies were excluded. Studies were checked for heterogeneity. A standard fixed-effect Bayesian network meta-analysis was conducted based on hazard ratios (HRs) and assuming proportional hazards for progression-free and overall survival (PFS/OS). Results: Seven eligible studies (1 Phase [Ph] 2, 5 Ph 3, 1 Ph 2/3) were identified. All had PFS data; five had OS data. Two trials compared F vs A; PFS data were available for both trials; sufficiently mature OS data for F were available from Ph 2 only. The proportional hazards assumption was met for PFS only.F had significantly improved PFS vs Tam (HR 0.57, 95% credibility interval [Crl] 0.44-0.73), A (HR 0.75, 95% Crl 0.62-0.91), E (HR 0.65, 95% Crl 0.47-0.91), and T (HR 0.53, 95% Crl 0.37-0.78). Numerically improved PFS was observed for F vs L (HR 0.81, 95% Crl 0.59-1.11). F had significantly improved OS vs Tam (HR 0.63, 95% Crl 0.40-0.98), A (HR 0.63, 95% Crl 0.42-0.94), and E (HR 0.56, 95% Crl 0.33-0.95). OS was numerically improved with F vs L (HR 0.66, 95% Crl 0.41-1.04). Conclusions: This analysis suggests improved PFS and OS for fulvestrant vs tamoxifen, anastrozole, exemestane, and letrozole, and PFS for fulvestrant vs toremifene. Further analysis should be conducted, using non-proportional hazard methods and more mature OS data, to confirm the OS results.
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Sharma, Reema, Richa Srivastava, and Satyanshu K. Upadhyay. "A Hierarchical Bayes Analysis and Comparison of PH Weibull and PH Exponential Models for One-Shot Device Testing Experiment." International Journal of Reliability, Quality and Safety Engineering 28, no. 05 (July 30, 2021): 2150036. http://dx.doi.org/10.1142/s0218539321500364.
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The one-shot devices are highly reliable and, therefore, accelerated life tests are often employed to perform the experiments on such devices. Obviously, in the process, some covariates are introduced. This paper considers the proportional hazards model to observe the effect of covariates on the failure rates under the assumption of two commonly used models, namely the exponential and the Weibull for the lifetimes. The Bayes implementation is proposed using the hybridization of Gibbs and Metropolis algorithms that routinely extend to missing data situations as well. The entertained models are compared using the Bayesian and deviance information criteria and the expected posterior predictive loss criterion. Finally, the results based on two real data examples are given as an illustration.
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Spirko-Burns, Lauren, and Karthik Devarajan. "Unified methods for feature selection in large-scale genomic studies with censored survival outcomes." Bioinformatics 36, no. 11 (March 10, 2020): 3409–17. http://dx.doi.org/10.1093/bioinformatics/btaa161.
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Abstract Motivation One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous datasets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards (PH), which is unlikely to hold for each feature. When applied to genomic features exhibiting some form of non-proportional hazards (NPH), these methods could lead to an under- or over-estimation of the effects. We propose a broad array of marginal screening techniques that aid in feature ranking and selection by accommodating various forms of NPH. First, we develop an approach based on Kullback–Leibler information divergence and the Yang–Prentice model that includes methods for the PH and proportional odds (PO) models as special cases. Next, we propose R2 measures for the PH and PO models that can be interpreted in terms of explained randomness. Lastly, we propose a generalized pseudo-R2 index that includes PH, PO, crossing hazards and crossing odds models as special cases and can be interpreted as the percentage of separability between subjects experiencing the event and not experiencing the event according to feature measurements. Results We evaluate the performance of our measures using extensive simulation studies and publicly available datasets in cancer genomics. We demonstrate that the proposed methods successfully address the issue of NPH in genomic feature selection and outperform existing methods. Availability and implementation R code for the proposed methods is available at github.com/lburns27/Feature-Selection. Contact karthik.devarajan@fccc.edu Supplementary information Supplementary data are available at Bioinformatics online.
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Tebbi, O., F. Guérin, and B. Dumon. "Standard Accelerated Life Testing Model Applied to Mechanical Components." Journal of the IEST 48, no. 1 (September 1, 2005): 103–14. http://dx.doi.org/10.17764/jiet.48.1.b0640u145jw81346.
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This paper provides an overview of the application of accelerated life testing (ALT) models to mechanical components. Estimates are based upon a classical test plan using a sample system tested under accelerated conditions (not under operating conditions). The time transfer regression model is considered log-linear. The parametric model, proportional hazards (PH) model, and semiparametric model are studied. This paper illustrates an experimental example on a paper clip.
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Khajehpiri, Boshra, Hamid Abrishami Moghaddam, Mohamad Forouzanfar, Reza Lashgari, Jaime Ramos-Cejudo, Ricardo S. Osorio, and Babak A. Ardekani. "Survival Analysis in Cognitively Normal Subjects and in Patients with Mild Cognitive Impairment Using a Proportional Hazards Model with Extreme Gradient Boosting Regression." Journal of Alzheimer's Disease 85, no. 2 (January 18, 2022): 837–50. http://dx.doi.org/10.3233/jad-215266.
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Background: Evaluating the risk of Alzheimer’s disease (AD) in cognitively normal (CN) and patients with mild cognitive impairment (MCI) is extremely important. While MCI-to-AD progression risk has been studied extensively, few studies estimate CN-to-MCI conversion risk. The Cox proportional hazards (PH), a widely used survival analysis model, assumes a linear predictor-risk relationship. Generalizing the PH model to more complex predictor-risk relationships may increase risk estimation accuracy. Objective: The aim of this study was to develop a PH model using an Xgboost regressor, based on demographic, genetic, neuropsychiatric, and neuroimaging predictors to estimate risk of AD in patients with MCI, and the risk of MCI in CN subjects. Methods: We replaced the Cox PH linear model with an Xgboost regressor to capture complex interactions between predictors, and non-linear predictor-risk associations. We endeavored to limit model inputs to noninvasive and more widely available predictors in order to facilitate future applicability in a wider setting. Results: In MCI-to-AD (n = 882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (n = 100) individuals, the C-index was 73.3%. In both applications, the C-index was statistically significantly higher in the Xgboost in comparison to the Cox PH model. Conclusion: Using non-linear regressors such as Xgboost improves AD dementia risk assessment in CN and MCI. It is possible to achieve reasonable risk stratification using predictors that are relatively low-cost in terms of time, invasiveness, and availability. Future strategies for improving AD dementia risk estimation are discussed.
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Tsai, Bor-Wen, John T. Harvey, and Carl L. Monismith. "Application of Weibull Theory in Prediction of Asphalt Concrete Fatigue Performance." Transportation Research Record: Journal of the Transportation Research Board 1832, no. 1 (January 2003): 121–30. http://dx.doi.org/10.3141/1832-15.
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The objectives are to present the feasibility of utilizing the Weibull proportional hazards (PH) model and the Weibull accelerated failure time model of survival analysis to predict in situ pavement fatigue performance from laboratory fatigue test results. A set of WesTrack temperature sensitivity fatigue tests is used as an example to demonstrate how the Weibull PH model works. An example utilizing the deflection data from a heavy vehicle simulator test is given to verify the feasibility of the failure time model. The relationship between mode factor and controlled-deformation fatigue test is discussed using the same example. The Weibull theory approach has potential for use in recursive mechanistic-empirical design procedures.
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Apeagee, Bemgba, P. O. Agada, D. A. Dzaar, and A. A. Ede. "APPLICATION OF COX PROPORTIONAL HAZARDS MODEL IN TIME TO EVENT ANALYSIS OF HIV/AIDS PATIENTS." FUDMA JOURNAL OF SCIENCES 4, no. 3 (September 12, 2020): 185–91. http://dx.doi.org/10.33003/fjs-2020-0403-360.
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The Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) remains a public health crisis that has contributed to the majority of deaths recorded in the past decade, affecting Nigeria and other countries of the world as it has become drug resistance in some patients. This study was aimed at estimating the effects of covariates on the survival time for HIV/AIDS patients using the Cox PH model. The KM results indicated that 91 patients were males, out of which 31 experienced the event of interest, and 60 (68.9%) were censored, 209 were females, 65 died due to AIDS, and 144 were censored (68.9%) respectively. The results of the Cox PHM indicated that sex, age, and health of patients are positively associated with death due to AIDS with the associated negative length of survival for HIV/AIDS patients with HR (1.149, 1.235, 1.887, and 1.306) respectively. The study concluded that CD4 cell counts are the only variable or covariate that showed a lower risk of death due to AIDS. The results further stated that patients with high CD4 cell counts have lower risks of death due to AIDS but an increase in survival time considering other factors. The study, therefore recommends that survival analysis should be used to assess the various risk factors and the confounding effects associated with them stressing that a patient’s lifestyle should be improved to live healthy as they continue to age older.
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Zhang, Tang, Yao-Zong Guan, and Hao Liu. "Association of Acidemia With Short-Term Mortality of Acute Myocardial Infarction: A Retrospective Study Base on MIMIC-III Database." Clinical and Applied Thrombosis/Hemostasis 26 (January 1, 2020): 107602962095083. http://dx.doi.org/10.1177/1076029620950837.
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Acute myocardial infarction (AMI) is a leading cause of death and not a few of these patients are combined with acidemia. This study aimed to detect the association of acidemia with short-term mortality of AMI patients. A total of 972 AMI patients were selected from the Medical Information Mart for Intensive Care (MIMIC) III database for analysis. Propensity-score matching (PSM) was used to reduce the imbalance. Kaplan-Meier survival analysis was used to compare the mortality, and Cox-proportional hazards model was used to detect related factors associated with mortality. After PSM, a total of 345 non-acidemia patients and 345 matched acidemia patients were included. The non-acidemia patients had a significantly lower 30-day mortality (20.0% vs. 28.7%) and lower 90-day mortality (24.9% vs. 31.9%) than the acidemia patients ( P < 0.001 for all). The severe-acidemia patients (PH < 7.25) had the highest 30-day mortality (52.6%) and 90-day mortality (53.9%) than non-acidemia patients and mild-acidemia (7.25 ≤ PH < 7.35) patients ( P < 0.001). In Cox-proportional hazards model, acidemia was associated with improved 30-day mortality (HR = 1.518; 95%CI = 1.110-2.076, P = 0.009) and 90-day mortality (HR = 1.378; 95%CI = 1.034 -1.837, P = 0.029). These results suggest that severe acidemia is associated with improved 30-day mortality and 90-day mortality of AMI patients.
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Asano, Junichi, Akihiro Hirakawa, Chikuma Hamada, Kan Yonemori, Taizo Hirata, Chikako Shimizu, Kenji Tamura, and Yasuhiro Fujiwara. "Use of Cox’s Cure Model to Establish Clinical Determinants of Long-Term Disease-Free Survival in Neoadjuvant-Chemotherapy-Treated Breast Cancer Patients without Pathologic Complete Response." International Journal of Breast Cancer 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/354579.
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In prognostic studies for breast cancer patients treated with neoadjuvant chemotherapy (NAC), the ordinary Cox proportional-hazards (PH) model has been often used to identify prognostic factors for disease-free survival (DFS). This model assumes that all patients eventually experience relapse or death. However, a subset of NAC-treated breast cancer patients never experience these events during long-term follow-up (>10 years) and may be considered clinically “cured.” Clinical factors associated with cure have not been studied adequately. Because the ordinary Cox PH model cannot be used to identify such clinical factors, we used the Cox PH cure model, a recently developed statistical method. This model includes both a logistic regression component for the cure rate and a Cox regression component for the hazard for uncured patients. The purpose of this study was to identify the clinical factors associated with cure and the variables associated with the time to recurrence or death in NAC-treated breast cancer patients without a pathologic complete response, by using the Cox PH cure model. We found that hormone receptor status, clinical response, human epidermal growth factor receptor 2 status, histological grade, and the number of lymph node metastases were associated with cure.
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Young, Virginia R. "Discussion of Christofides' Conjecture Regarding Wang's Premium Principle." ASTIN Bulletin 29, no. 2 (November 1999): 191–95. http://dx.doi.org/10.2143/ast.29.2.504610.
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Christofides (1998) studies the proportional hazards (PH) transform of Wang (1995) and shows that for some parametric families, the PH premium principle reduces to the standard deviation (SD) premium principle. Christofides conjectures that for a parametric family of distributions with constant skewness, the PH premium principle reduces to the SD principle. I will show that this conjecture is false in general but that it is true for location-scale families and for certain other families.Wang's premium principle has been established as a sound measure of risk in Wang (1995, 1996), Wang, Young, and Panjer (1997), and Wang and Young (1998). Determining when the SD premium principle is a special case of Wang's premium principle is important because it will help identify circumstances under which the more easily applied SD premium principle is a reliable measure of risk.First, recall that a distortion g is a non-decreasing function from [0, 1] onto itself. Wang's premium principle, with a fixed distortion g, associates the following certainty equivalent with a random variable X, (Wang, 1996) and (Denneberg, 1994):in which Sx is the decumulative distribution function (ddf) of X, Sx(t) = Pr(X > t), t ∈ R. If g is a power distortion, g(p) = pc, then Hg is the proportional hazards (PH) premium principle (Wang, 1995).Second, recall that a location-scale family of ddfs is , in which Sz is a fixed ddf. Alternatively, if Z has ddf Sz, then {X = μ + σZ: μ∈ R, σ > 0} forms a location-scale family of random variables, and the ddf of . Examples of location-scale families include the normal, Cauchy, logistic, and uniform families (Lehmann, 1991, pp. 20f). In the next proposition, I show that Wang's premium principle reduces to the SD premium principle on a location-scale family. Christofides (1998) observes this phenomenon in several special cases.
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Shah, Ronak Jagdeep, Lisa E. Vaughan, Felicity T. Enders, Dawn S. Milliner, and John C. Lieske. "Plasma Oxalate as a Predictor of Kidney Function Decline in a Primary Hyperoxaluria Cohort." International Journal of Molecular Sciences 21, no. 10 (May 20, 2020): 3608. http://dx.doi.org/10.3390/ijms21103608.
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This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8–115), 3a (HR 13.7, 95% CI 3.0–62), and 3b stages (HR 5.2, 95% CI 1.1–25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1–Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.
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Royston, Patrick. "Power and sample-size analysis for the Royston–Parmar combined test in clinical trials with a time-to-event outcome." Stata Journal: Promoting communications on statistics and Stata 18, no. 1 (March 2018): 3–21. http://dx.doi.org/10.1177/1536867x1801800102.
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Randomized controlled trials with a time-to-event outcome are usually designed and analyzed assuming proportional hazards (PH) of the treatment effect. The sample-size calculation is based on a log-rank test or the nearly identical Cox test, henceforth called the Cox/log-rank test. Nonproportional hazards (non-PH) has become more common in trials and is recognized as a potential threat to interpreting the trial treatment effect and the power of the log-rank test—hence to the success of the trial. To address the issue, in 2016, Royston and Parmar ( BMC Medical Research Methodology 16: 16) proposed a “combined test” of the global null hypothesis of identical survival curves in each trial arm. The Cox/log-rank test is combined with a new test derived from the maximal standardized difference in restricted mean survival time (RMST) between the trial arms. The test statistic is based on evaluations of the between-arm difference in RMST over several preselected time points. The combined test involves the minimum p-value across the Cox/log-rank and RMST-based tests, appropriately standardized to have the correct distribution under the global null hypothesis. In this article, I introduce a new command, power_ct, that uses simulation to implement power and sample-size calculations for the combined test. power_ct supports designs with PH or non-PH of the treatment effect. I provide examples in which the power of the combined test is compared with that of the Cox/log-rank test under PH and non-PH scenarios. I conclude by offering guidance for sample-size calculations in time-to-event trials to allow for possible non-PH.
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Ren, Yi, Chung-Chou H. Chang, Gabriel L. Zenarosa, Heather E. Tomko, Drew Michael S. Donnell, Hyung-joo Kang, Mark S. Roberts, and Cindy L. Bryce. "Gray’s Time-Varying Coefficients Model for Posttransplant Survival of Pediatric Liver Transplant Recipients with a Diagnosis of Cancer." Computational and Mathematical Methods in Medicine 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/719389.
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Transplantation is often the only viable treatment for pediatric patients with end-stage liver disease. Making well-informed decisions on when to proceed with transplantation requires accurate predictors of transplant survival. The standard Cox proportional hazards (PH) model assumes that covariate effects are time-invariant on right-censored failure time; however, this assumption may not always hold. Gray’s piecewise constant time-varying coefficients (PC-TVC) model offers greater flexibility to capture the temporal changes of covariate effects without losing the mathematical simplicity of Cox PH model. In the present work, we examined the Cox PH and Gray PC-TVC models on the posttransplant survival analysis of 288 pediatric liver transplant patients diagnosed with cancer. We obtained potential predictors through univariable(P<0.15)and multivariable models with forward selection(P<0.05)for the Cox PH and Gray PC-TVC models, which coincide. While the Cox PH model provided reasonable average results in estimating covariate effects on posttransplant survival, the Gray model using piecewise constant penalized splines showed more details of how those effects change over time.
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Janz, Tyler A., Evan M. Graboyes, Shaun A. Nguyen, Mark A. Ellis, David M. Neskey, E. Emily Harruff, and Eric J. Lentsch. "A Comparison of the NCDB and SEER Database for Research Involving Head and Neck Cancer." Otolaryngology–Head and Neck Surgery 160, no. 2 (August 21, 2018): 284–94. http://dx.doi.org/10.1177/0194599818792205.
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Objective To determine whether structural differences in data sampling between the National Cancer Database (NCDB), a non-population-based cancer registry, and Surveillance, Epidemiology, and End Results (SEER), a population-based cancer registry, result in differences in patient characteristics or oncologic outcomes. Study Design Retrospective cohort study. Setting NCDB and SEER database. Subjects and Methods Patients with head and neck cancer (HNC) were included from 2004 to 2014. The primary outcome, weighted differences in characteristics between the databases, was evaluated for each head and neck subsite (oral cavity [OC], oropharynx [OP], hypopharynx [HP], and larynx [LX]). The secondary outcome measure, overall survival (OS), was evaluated using Kaplan-Meier (KM) estimates of survival and Cox proportional hazards (PH) regression modeling. Results In total, 112,007 and 340,420 HNC cases were registered in SEER and the NCDB, respectively. The mean age at diagnosis for the 4 head and neck subsites differed by no more than 1.1 years between the 2 databases. The largest difference in patient or tumor characteristics was the frequency of OC subsite lip cancer (weighted proportional difference, 6.9%; 95% confidence interval, 6.5%-7.3%). Unadjusted KM estimates of 5-year OS differed by no more than 2% (OP, HP, and LX subsites). On Cox PH modeling, adjusted hazard ratios ranged from 0.89 to 0.91 for patients of different head and neck subsites in the NCDB relative to SEER. Conclusions Patients with HNC in the SEER database and NCDB do not greatly differ in terms of demographics, treatment, and survival. Decisions to use either database should be driven by the data fields, which vary between the registries.
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Mohammed, Mohanad, Innocent B. Mboya, Henry Mwambi, Murtada K. Elbashir, and Bernard Omolo. "Predictors of colorectal cancer survival using cox regression and random survival forests models based on gene expression data." PLOS ONE 16, no. 12 (December 29, 2021): e0261625. http://dx.doi.org/10.1371/journal.pone.0261625.
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Understanding and identifying the markers and clinical information that are associated with colorectal cancer (CRC) patient survival is needed for early detection and diagnosis. In this work, we aimed to build a simple model using Cox proportional hazards (PH) and random survival forest (RSF) and find a robust signature for predicting CRC overall survival. We used stepwise regression to develop Cox PH model to analyse 54 common differentially expressed genes from three mutations. RSF is applied using log-rank and log-rank-score based on 5000 survival trees, and therefore, variables important obtained to find the genes that are most influential for CRC survival. We compared the predictive performance of the Cox PH model and RSF for early CRC detection and diagnosis. The results indicate that SLC9A8, IER5, ARSJ, ANKRD27, and PIPOX genes were significantly associated with the CRC overall survival. In addition, age, sex, and stages are also affecting the CRC overall survival. The RSF model using log-rank is better than log-rank-score, while log-rank-score needed more trees to stabilize. Overall, the imputation of missing values enhanced the model’s predictive performance. In addition, Cox PH predictive performance was better than RSF.
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Nik Ab Kadir, Mohd Nasrullah, Najib Majdi Yaacob, Siti Norbayah Yusof, Imi Sairi Ab Hadi, Kamarul Imran Musa, Seoparjoo Azmel Mohd Isa, Balqis Bahtiar, Farzaana Adam, Maya Mazuwin Yahya, and Suhaily Mohd Hairon. "Development of Predictive Models for Survival among Women with Breast Cancer in Malaysia." International Journal of Environmental Research and Public Health 19, no. 22 (November 20, 2022): 15335. http://dx.doi.org/10.3390/ijerph192215335.
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Prediction of survival probabilities based on models developed by other countries has shown inconsistent findings among Malaysian patients. This study aimed to develop predictive models for survival among women with breast cancer in Malaysia. A retrospective cohort study was conducted involving patients who were diagnosed between 2012 and 2016 in seven breast cancer centres, where their survival status was followed until 31 December 2021. A total of 13 predictors were selected to model five-year survival probabilities by applying Cox proportional hazards (PH), artificial neural networks (ANN), and decision tree (DT) classification analysis. The random-split dataset strategy was used to develop and measure the models’ performance. Among 1006 patients, the majority were Malay, with ductal carcinoma, hormone-sensitive, HER2-negative, at T2-, N1-stage, without metastasis, received surgery and chemotherapy. The estimated five-year survival rate was 60.5% (95% CI: 57.6, 63.6). For Cox PH, the c-index was 0.82 for model derivation and 0.81 for validation. The model was well-calibrated. The Cox PH model outperformed the DT and ANN models in most performance indices, with the Cox PH model having the highest accuracy of 0.841. The accuracies of the DT and ANN models were 0.811 and 0.821, respectively. The Cox PH model is more useful for survival prediction in this study’s setting.
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Hsu, Vivien M., Lorinda Chung, Laura K. Hummers, Ami Shah, Robert Simms, Marcy Bolster, Faye N. Hant, et al. "Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry." Journal of Rheumatology 46, no. 2 (October 1, 2018): 176–83. http://dx.doi.org/10.3899/jrheum.180018.
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Objective.We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).Methods.The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.Results.Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4–8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.Conclusion.Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.
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Machado, Roberto, Martin Steinberg, Duane Bonds, Samir Ballas, William Blackwelder, Bruce Barton, Myron Waclawiw, Oswaldo Castro, and Mark Gladwin. "Natriuretic Peptide Levels Correlate with Pulmonary Pressures and Prospective Mortality in SCD: Use of This Biomarker To Identify Prevalence and Mortality of Pulmonary Hypertension in the MSH Cohort." Blood 106, no. 11 (November 16, 2005): 1. http://dx.doi.org/10.1182/blood.v106.11.1.1.
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Abstract Pulmonary hypertension [PH-tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s] is a common complication of sickle cell disease associated with high mortality. Identification of biomarkers of PH and mortality could facilitate screening and risk stratification in this population. Validated biomarkers would provide methods for retrospective evaluation of the prevalence and prognosis of PH in large historical cohorts of patients such as the Multicenter Study of Hydroxyurea in Sickle Cell Anemia(MSH). Because brain natriuretic peptide(BNP) is released from the ventricles during pressure strain, we hypothesized that BNP levels would correlate with the severity of PH and prospective risk of death in patients with SCD. BNP was measured in 45 African-American control subjects and 230 patients with SCD. Median (interquartile range) BNP(pg/ml) was higher in patients with PH than patients without PH or controls[+PH: 206(81–701),-PH: 47(26–104), C: 29, P<0.001]. BNP levels directly correlated with age (R=0.32, P<0.001), creatinine (R=0.22, P<0.001), LDH(R=0.31, P<0.001), TRV (R=0.5, P<0.001), pulmonary vascular resistance (R=0.5, P=0.001); and inversely with hemoglobin(R=0.41, P<0.001), cardiac output(R=0.47, P= 0.003) and 6-minute walk distance(R=0.51, P=0.001). The area under the ROC for BNP and the diagnosis of pulmonary hypertension was 0.84 (P<0.001). A cutoff value of 160 pg/ml (corresponding to the 75th percentile for the population) had 58% sensitivity and 98% specificity for the diagnosis of PH. Cox proportional hazards regression identified BNP as an independent predictor of mortality(RR 2.17,95% CI 1.2–3.8, P =0.001) with clear mortality break point at the 75th percentile(160 pg/ml). To independently explore the prevalence and associated risk of PH in patients with sickle cell disease, a BNP value of 160 pg/ml was used as an indicator of PH. BNP levels were then measured in plasma samples collected in 121 patients who were enrolled in the MSH patient’s follow-up study that started in 1996. These patients had received hydroxyurea or placebo for two years, had moderately severe disease based on study entry criteria, and had 9-years of comprehensive follow-up. An abnormal BNP level ≥160 pg/ml was present in 30% of patients in the MSH cohort. BNP levels correlated directly with age(R=0.35, P<0.001) and creatinine (R=0.24, P<0.001), and inversely with hemoglobin(R=−0.54, P<0.001). There was no correlation between BNP and rate of painful episodes or acute chest syndrome, use of hydroxyurea or leukocyte count. A high BNP level in the MSH cohort was associated with mortality by logistic regression(OR 3.04,95% CI 1.2–7.6, P = 0.018) and Cox proportional hazards regression analysis(RR 2.87, P=0.017). The relationship remained significant for continuous log- transformed BNP values and after adjustment for other covariates. These studies confirm that PH is common, mechanistically linked to hemolytic anemia and the major risk factor for death in SCD. Provocatively, the MSH analysis suggests that rates of pain episodes in this small sample of seriously ill patients were unrelated to risk of death: this risk was largely determined by a high BNP level, which is probably explained by undiagnosed hemolysis-associated PH.
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Ou, Shuo-Ming, Wen-Chien Fan, Kun-Ta Cho, Chiu-Mei Yeh, Vincent Yi-Fong Su, Man-Hsin Hung, Yu-Sheng Chang, et al. "Systemic Sclerosis and the Risk of Tuberculosis." Journal of Rheumatology 41, no. 8 (July 15, 2014): 1662–69. http://dx.doi.org/10.3899/jrheum.131125.
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Objective.Pulmonary involvement is common in patients with systemic sclerosis (SSc), and this condition causes substantial morbidity and mortality. Disrupted immunity from the disease or associated medication may render such patients subject to tuberculosis (TB) infection. However, the relationship between SSc and TB has not yet been investigated.Methods.Using the Taiwan National Health Insurance Research Database, 838 patients with SSc diagnosed in Taiwan during 2000–2006 were identified and followed for emergence of TB infection. Incidence rate ratios (IRR) of TB compared to 8380 randomly selected age-, sex-, and comorbidity-matched controls without SSc were calculated. The Cox proportional hazards model was used for multivariate adjustment to identify independent risk factors for TB infection.Results.The risk of TB infection was higher in the SSc cohort than in controls (IRR 2.81, 95% CI 1.36–5.37; p = 0.004), particularly for pulmonary TB (IRR 2.53, 95% CI 1.08–5.30; p = 0.022). Other independent risk factors for TB infection in patients with SSc were age ≥ 60 years [hazard ratio (HR) 3.52, 95% CI 1.10–11.33; p = 0.035] and pulmonary hypertension (PH; HR 6.06, 95% CI 1.59–23.17; p = 0.008). Mortality did not differ for SSc patients with or without TB.Conclusion.In this nationwide study, the incidence of TB infection was significantly higher among patients with SSc than in controls without SSc. Special care should be taken in managing patients with SSc who are at high risk for TB, especially those aged ≥ 60 years or who also have PH.
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Lara, Matthew Stephen, Ann Brunson, Ben Kent Tomlinson, Theodore Wun, Lihong Qi, Rosemary Cress, Primo Lara, David R. Gandara, and Karen Kelly. "Predictors of survival for younger patients (pts) less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry (CCR) analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8049. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8049.
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8049 Background: Lung cancer is often seen in older pts, with a median age at diagnosis of 70 years (yrs). Epidemiology and outcomes are reportedly different among younger NSCLC pts (< 50 yrs). We hypothesized that these pts have longer cause-specific survival (CSS) and that baseline clinical features prognostic for CSS would be identified. Methods: NSCLC pts in the CCR diagnosed between 1/98 through 12/09 were included. The primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables. Results: We identified 132,671 lung cancer pts: 114,451 (86.3%) had NSCLC. 6,389 (5.6%) were < 50 yrs (median, 46 yrs). Demographics: White (3,557, 56%); Histology: AdenoCA (AC) (3,406, 53%), Squamous (781, 12%), BAC (291, 4.6%); Stage IV (3,655, 57%). Fewer pts < 50 yrs were diagnosed in later yrs: from 37% in ‘98-’01 to 29% in ‘06-‘09. Results of Cox PH models for all ages and < 50 years are shown. Conclusions: The relative proportion of pts < 50 yrs has declined by 22% over the past decade. Age < 50 years was an independent predictor of improved CSS (HR 0.83, p<0.001). In younger pts, AC histology was not prognostic for CSS (versus squamous) despite known differences in clinical and biologic behavior between subtypes.Importantly, clinical variables strongly prognostic for CSS were identified in pts < 50 yrs. [Table: see text]
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Yin, Minyue, Jiaxi Lin, Lu Liu, Jingwen Gao, Wei Xu, Chenyan Yu, Shuting Qu, et al. "Development of a Deep Learning Model for Malignant Small Bowel Tumors Survival: A SEER-Based Study." Diagnostics 12, no. 5 (May 17, 2022): 1247. http://dx.doi.org/10.3390/diagnostics12051247.
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Background This study aims to explore a deep learning (DL) algorithm for developing a prognostic model and perform survival analyses in SBT patients. Methods The demographic and clinical features of patients with SBTs were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We randomly split the samples into the training set and the validation set at 7:3. Cox proportional hazards (Cox-PH) analysis and the DeepSurv algorithm were used to develop models. The performance of the Cox-PH and DeepSurv models was evaluated using receiver operating characteristic curves, calibration curves, C-statistics and decision-curve analysis (DCA). A Kaplan–Meier (K–M) survival analysis was performed for further explanation on prognostic effect of the Cox-PH model. Results The multivariate analysis demonstrated that seven variables were associated with cancer-specific survival (CSS) (all p < 0.05). The DeepSurv model showed better performance than the Cox-PH model (C-index: 0.871 vs. 0.866). The calibration curves and DCA revealed that the two models had good discrimination and calibration. Moreover, patients with ileac malignancy and N2 stage disease were not responding to surgery according to the K–M analysis. Conclusions This study reported a DeepSurv model that performed well in CSS in SBT patients. It might offer insights into future research to explore more DL algorithms in cohort studies.
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Jones, Clare Frances, Giles Monnickendam, Mingshu Zhu, and Jan McKendrick. "Can we satisfactorily measure the clinical value of new oncology agents with a single summary measure?" Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6606. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6606.
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6606 Background: Current value frameworks (VFs) assess clinical value primarily through using clinical trial endpoints as survival metrics (e.g., median and hazard ratio (HR)). But, if key assumptions do not hold, the interpretation of these summary statistics can become problematic and fail to adequately capture the expected benefit to a patient. This has been observed with innovative oncology treatments. As a proof of concept analysis, we reviewed how two VFs (ASCO and ESMO) dealt with cases where the assumption of proportional hazards (PH) does not hold. Methods: Oncology agents approved by the FDA since 2011 were reviewed and three agents were identified with survival profiles where the assumption of PH was found not to hold because, on visual inspection, the survival curves displayed non-standard patterns: Divergence followed by convergence – panobinostat OS in RRMM; Curves initially track together then diverge – nivolumab OS in NSCLC; Curves diverge steadily then a plateau emerged in the active treatment curve – pembrolizumab PFS in refractory melanoma. We evaluated these agents to assess which measures of clinical benefit were most valued under each VF and how the issue of non-PH influenced the outcome. Results: Clinical benefit/value scores varied: ASCO: 14-27 (maximum 100), ESMO: grade 1-3. The ASCO VF uses a hierarchical approach (incorporating HR and median survival benefit, always prioritising the former) adding a bonus for survival benefit in the tail of the distribution. The combination of HR, median survival benefit 2 and 3 year survival rates in the ESMO non-curative VF can potentially capture aspects of clinical benefit in some cases of non-PH. Overall, the ASCO VF appears less flexible to accommodate non-PH than the ESMO VF. Conclusions: Despite VFs using summary statistics which cannot be easily interpreted under conditions of non-PH, the case of non-PH is not explicitly catered for. Additionally, both VFs may miss important interpretation where value is differentiated across patients groups with different response profiles which may underlie non-standard survival curves. In these situations, a more flexible approach to assessing clinical value may render VFs more relevant for clinical decision making.
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Nevskaya, T., Y. Jiang, M. Wang, M. Baron, J. Pope, Janet E. Pope, Murray Baron, et al. "FRI0258 CUMULATIVE INCIDENCE, SURVIVAL AND PREDICTORS OF PULMONARY HYPERTENSION IN SYSTEMIC SCLEROSIS SUBSETS: PAH IS NOT INCREASED IN LIMITED VS DIFFUSE PATIENTS BY ADJUSTED COMPETING RISK ANALYSIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 713. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3847.
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Background:Pulmonary hypertension (PH) is a life-threatening complication of systemic sclerosis (SSc), thought to be more commonly found in limited cutaneous (lcSSc) compared to diffuse (dcSSc) subset. Since lcSSc has a better prognosis, it is unclear whether a higher occurrence of PH in lcSSc reflects survival bias.Objectives:To compare the cumulative PH incidence in disease subsets, after accounting for death as a competing event, in a large multi-center SSc cohort.Methods:Cumulative incidence of PH was studied in 1431 Canadian Scleroderma Research Group (CSRG) database patients (57% lcSSc; follow-up 3.5±2.9 years, range 1-14) by Fine-Gray analysis, unadjusted and adjusted for sex, age and SSc-related autoantibodies (SAS 9.4). Survival curves, predictors of PH development and survival were analyzed by Kaplan-Meier and Cox proportional hazards analyses (SPSS 25.0). Subgroup analysis was performed for PAH.Results:157 SSc patients had PH (including 117 PAH), either confirmed by RHC or postmortem. Compared to those without PH, lcSSc-PH patients had longer disease and older age at SSc diagnosis, while dcSSc-PH patients - more severe peripheral vascular and gastrointestinal involvement. The cumulative incidences of PH/PAH were similar in dcSSc and lcSSc after accounting for death in the adjusted competitive risk model (Table 1; Fig.1). 47% of PH- and 42% of PAH-patients died over a FU period. Male gender (p<0.0001) and anti-Scl-70 (p<0.001) were associated with earlier PH development, while older age (p=0.006) - with PAH (Table 2). ACA-negativity and older age predicted worse PH prognosis.Figure 1.Cumulative incidence curves for PH (A) and PAH (B).Conclusion:Cumulative incidence of PH, after accounting for death as competing event, was comparable in SSc subsets. Vigilance should be considered in males, Scl-70 positive and late age-onset SSc.Table 1.Sub-distribution Hazard ratio of incident PH and PAH.PHPAHHazard ratio (95% CIs)P valuesHazard ratio (95% CIs)P valuesCrude ModelDcSSc vs lcSSc2.03 (1.13, 3.66)0.01861.60 (0.82, 3.16)0.1710Adjusted modelDcSSc vs lcSSc1.82 (0.93, 3.57)0.08181.57 (0.69, 3.59)0.2812Female vs male0.98 (0.42, 2.32)0.96602.10 (0.51, 8.65)0.3040Age1.00 (0.99, 1.02)0.70411.01 (0.98, 1.03)0.5498AntibodiesACA vs negative0.95 (0.46, 1.96)0.89911.08 (0.50, 2.35)0.8391ATA vs negative1.93 (0.84, 4.42)0.11980.59 (0.13, 2.73)0.4970Anti-RNAP vs negative1.24 (0.45, 3.43)0.68411.77 (0.58, 5.44)0.3181Disclosure of Interests:Tatiana Nevskaya: None declared, Yuxuan Jiang: None declared, Mianbo Wang: None declared, Murray Baron: None declared, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB
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Kohne, Claus-Henning, Ralf Hofheinz, Laurent Mineur, Henry Letocha, Richard Greil, Josef Thaler, Brian Twomey, et al. "Amphiregulin (AREG) expression and response to first-line panitumumab (pmab) plus FOLFIRI in metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 731. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.731.
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731 Background: Biomarker analyses have shown that patients (pts) with RAS wild-type (WT) mCRC can achieve overall survival (OS) benefits with first-line pmab plus chemotherapy. Other biomarkers may exist that could optimize pt selection. Epidermal growth factor receptor ligand (eg AREG) levels have been correlated with OS during anti-EGFR therapy. Here we investigate the relationship between AREG expression and treatment outcome in a single-arm first-line mCRC study of pmab + FOLFIRI. Methods: Qualified reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure AREG RNA expression in archival formalin-fixed, paraffin embedded tumor samples from mCRC pts in two pmab trials (STEPP and 314). The STEPP analysis was used to establish a cut-off point in AREG expression that identified the best responders. This cut-off was applied prospectively to samples previously analyzed for KRAS in the 314 trial. Using the KRASMT subgroup as a non-responding comparator, Cox proportional hazards (PH) models were used to evaluate AREG expression levels as a continuous covariate. Decision curves were used to estimate the progression-free survival (PFS) hazard ratio (HR) with increasing levels of baseline AREG expression. Results: In the 314 trial 100 pts had evaluable AREG levels. Among 50 KRAS WT pts, high AREG expression was associated with objective response (OR) (Table). The high AREG group had better PFS HRs (KRAS WT/KRAS MT: 0.30 [95% CI, 0.12–0.75]) compared with the low AREG group (PFS HR 0.49 [95% CI 0.21–1.1]). There was a significant biomarker-by-AREG expression interaction in the Cox PH model (p=0.03). Conclusions: Treatment decision curves based on the PH model suggest that most KRAS WT patients express AREG at levels where treatment benefit is predicted. Future analysis of samples from a RASWT population may provide further insights. Clinical trial information: NCT00508404. [Table: see text]
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MEKKI, Reem Yousif, Mohamed Hassan MUDAWI, Manahil Saidahmed MUSTAFA, Altaiyb Omer Ahmed MOHMMED, Ahmed Bakheet Abd ALLA, and Abdel Rahman AHMED. "Parametric Survival Models of Hemodialysis Patients in Relation with Patient-Related Factors." Medicina Moderna - Modern Medicine 27, no. 4 (December 20, 2020): 295–304. http://dx.doi.org/10.31689/rmm.2020.27.4.295.
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Background: Survival analysis refers to analyzing of statistical data for which the outcome variable of interest is time until an event occurs. This research aimed at comparing different models of parametric Proportional Hazards (PH) models (Weibull, exponential, Gompertz) in patients with hemodialysis to determine the best model for assessing the survival of patient. Study consists of 325 hemodialysis patients who referred to public hospitals in Khartoum state in the period from December 2005 to December 2015. Data was used to estimate the survival function with view to identify risk factors influencing among end-stage renal disease (ESRD) population. Based on the Cox-Snell Residuals and AIC, BIC, and Gompertz (PH) model is an efficient model than other when the values of (AIC=662.21), (BIC=703.83) and (R2=0.211) where maintained Study assessed that the variables dealing with univariate models were significant but had a significant effect on hemodialysis survival. The Gompertz model had the smallest AIC and BIC value; therefore; it was selected as the most appropriate model. In multivariable analysis, the BIC had the lowest value and the highest value in each analysis. The study assessed that diabetes mellitus and hypertension, regular, and hospital, had a. significant effect.
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Wang, Xiaoyan, Rohit P. Ojha, Sonia Partap, and Kimberly J. Johnson. "The effect of insurance status on overall survival among children and adolescents with cancer." International Journal of Epidemiology 49, no. 4 (June 23, 2020): 1366–77. http://dx.doi.org/10.1093/ije/dyaa079.
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Abstract Background Differences in access, delivery and utilisation of health care may impact childhood and adolescent cancer survival. We evaluated whether insurance coverage impacts survival among US children and adolescents with cancer diagnoses, overall and by age group, and explored potential mechanisms. Methods Data from 58 421 children (aged ≤14 years) and adolescents (15–19 years), diagnosed with cancer from 2004 to 2010, were obtained from the National Cancer Database. We examined associations between insurance status at initial diagnosis or treatment and diagnosis stage; any treatment received; and mortality using logistic regression, Cox proportional hazards (PH) regression, restricted mean survival time (RMST) and mediation analyses. Results Relative to privately insured individuals, the hazard of death (all-cause) was increased and survival months were decreased in those with Medicaid [hazard ratio (HR) = 1.27, 95% confidence interval (CI): 1.22 to 1.33; and −1.73 months, 95% CI: −2.07 to −1.38] and no insurance (HR = 1.32, 95% CI: 1.20 to 1.46; and −2.13 months, 95% CI: −2.91 to −1.34). The HR for Medicaid vs. private insurance was larger (pinteraction <0.001) in adolescents (HR = 1.52, 95% CI: 1.41 to 1.64) than children (HR = 1.16, 95% CI: 1.10 to 1.23). Despite statistical evidence violation of the PH assumption, RMST results supported all interpretations. Earlier diagnosis for staged cancers in the Medicaid and uninsured populations accounted for an estimated 13% and 19% of the survival deficit, respectively, vs. the privately insured population. Any treatment received did not account for insurance-associated survival differences in children and adolescents with cancer. Conclusions Children and adolescents without private insurance had a higher risk of death and shorter survival within 5 years following cancer diagnosis. Additional research is needed to understand underlying mechanisms.
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Zhu, Yingying, Xiaohan Li, Chunyan Da, Panyu Liang, Shuangshuang Jin, and Changbo Tang. "Effects of Cyclocarya paliurus (Batal.) Extracts on Oxidative Stability and Sensory Quality in Meat Products (Frankfurters)." Foods 11, no. 22 (November 19, 2022): 3721. http://dx.doi.org/10.3390/foods11223721.
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Oxidation is one of the most common causes of the deterioration of meat and meat products. At the same time, synthetic antioxidants are becoming less accepted by consumers due to the potential health hazards they might cause. Therefore, a new trend to substitute these synthetic antioxidants with natural antioxidants has emerged. This study adds flavonoid extracts from Cyclocarya paliurus (C. paliurus) as a natural antioxidant for meat products (Frankfurters). The results showed that flavonoid extracts from C. paliurus had strong antioxidant and antibacterial activity. This is proportional to concentration, and the addition of extracts could significantly (p < 0.05) delay the lipid oxidation in the samples. In addition, we did not observe hazardous effects on the samples’ pH and texture as a result of adding flavonoid extracts. We observed that flavonoid extracts from C. paliurus at concentrations of 0.06% and 0.12% did not affect the color and sensory evaluation of the samples. At a concentration of 0.18% and 0.24%, the flavonoid extracts had a negative impact on the color and sensory evaluation of the samples, likely due to the yellow-brown color of the extract itself. The findings showed that a low concentration of 0.12% flavonoid extracts from C. paliurus in meat products could effectively prevent lipid oxidation without affecting the sensory quality.
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Udland, Carley J., William A. Carey, Amy L. Weaver, Kristin C. Mara, Reese H. Clark, and Kevin R. Ellsworth. "Birth Size and Gestational Age Specific Outcomes of Inhaled Nitric Oxide Therapy in Preterm Neonates with Clinically Diagnosed Pulmonary Hypertension." American Journal of Perinatology 36, no. 14 (January 23, 2019): 1471–80. http://dx.doi.org/10.1055/s-0039-1677799.
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Objective Among neonates of 22 to 29 weeks' gestational age (GA) who required mechanical ventilation for the treatment of respiratory distress syndrome (RDS) and clinically diagnosed pulmonary hypertension (PH), we tested our hypothesis that the association between early treatment with inhaled nitric oxide (iNO) and survival would vary according to birth size and GA. Study Design Because iNO was not randomly prescribed to patients in this cohort, we used propensity score matching to pair a neonate who received iNO at a chronological age of ≤7 days with an unexposed neonate with similar baseline characteristics. The primary outcome was inhospital mortality, which we evaluated based on size for GA and GA strata using the Cox proportional hazards regression model. Results Among 1,531 neonates who met study criteria, we created a propensity score matched cohort of 615 pairs of neonates (iNO-exposed and unexposed). The risk of inhospital mortality for iNO-exposed neonates was observed only in the minority (<10%) who were large for GA, though this finding did not persist when matching for illness severity. Conclusion Early treatment with iNO is not associated with survival in most extremely premature neonates with RDS and clinically diagnosed PH when stratified for birth size or GA.
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Morin, Amy A., Alisha Albert-Green, Douglas G. Woolford, and David L. Martell. "The use of survival analysis methods to model the control time of forest fires in Ontario, Canada." International Journal of Wildland Fire 24, no. 7 (2015): 964. http://dx.doi.org/10.1071/wf14158.
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This paper presents the results from employing survival analysis methods to model the probability distribution of the control time of forest fires. The Kaplan–Meier estimator, log–location–scale models, accelerated failure time models, and Cox proportional hazards (PH) models are described. Historical lightning and people-caused forest fire data from the Province of Ontario, Canada from 1989 through 2004 are employed to illustrate the use of the Cox PH model. We demonstrate how this methodology can be used to examine the association between the control time of a suppressed forest fire and local factors such as weather, vegetation and fuel moisture, as well as fire management variables including the response time between when a fire is reported and the initiation of suppression action. Significant covariates common to both the lightning and people-caused models were the size of the fire at the onset of initial attack, the Fine Fuel Moisture Code and the Initial Spread Index. The response time was also a significant predictor for the control time of lightning-caused fires, whereas the Drought Code and time of day of initial attack were significant for people-caused fires. Larger values of the covariates in these models were associated with larger survival probabilities.
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Lv, Zhen-Chun, Fei Li, Lan Wang, Qin-Hua Zhao, Gong-Su Gang, Yue Wu, Yu-Qing Miao, and Ping Yuan. "Impact of Parthanatos on the Increased Risk of Onset and Mortality in Male Patients With Pulmonary Hypertension." American Journal of Men's Health 15, no. 3 (May 2021): 155798832110294. http://dx.doi.org/10.1177/15579883211029458.
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There have been no studies as to whether parthanatos, a poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1)-dependent and apoptosis-inducing factor (AIF)-mediated caspase-independent programmed cell death, is present in pulmonary hypertension (PH). Basic studies have, however, been conducted on several of the key molecules in parthanatos, such as PARP-1, AIF, and macrophage migration inhibitory factor (MIF). For this study, we collected blood samples from 88 incident male patients with PH and 50 healthy controls at the Shanghai Pulmonary Hospital. We measured the key factors of parthanatos (PARP-1, PAR, AIF, and MIF) by enzyme-linked immunosorbent assay and performed a logistic regression, Cox proportional hazards analysis, and Kaplan–Meier test to assess the prognostic value of the key molecules in diagnosing and predicting survival. The patients who ultimately died had a significantly poorer clinical status during the study than those who survived. The PARP-1, PAR, AIF, and MIF levels were significantly higher in the patients than in the controls (all p < .0001), and the PARP-1, PAR, and AIF levels were higher in the nonsurvivors than in the survivors (all p < .0001). PARP-1 and AIF levels served as independent predictors of disease onset and mortality in these patients (all p < .005). Patients with PARP-1 levels <11.24 ng/mL or AIF levels <1.459 pg/mL had significantly better survival than those with higher PARP-1 or AIF levels ( p < .0001). Circulating levels of PARP-1 and AIF were independent predictors for PH onset and mortality, which indicated that parthanatos might be associated with the pathogenesis of PH.
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Ma, Ting Martin, Fang-I. Chu, Tahmineh Romero, Jeff M. Michalski, Thomas Michael Pisansky, Mack Roach, Felix Y. Feng, et al. "Local failure, distant metastasis, and survival after definitive radiotherapy for intermediate- and high-risk prostate cancer: An individual patient-level meta-analysis of 18 randomized trials." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 277. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.277.
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277 Background: The prognostic importance of local failure (LF) after definitive radiotherapy (RT) in patients with NCCN intermediate- (IRPCa) and high-risk prostate cancer (HRPCa) remains unclear, particularly given the likelihood that occult distant metastases (DMs) at presentation may be the true driver of natural history. Here, we leverage individual patient data (IPD) from 18 randomized control trials (RCTs) to evaluate the prognostic impact of LF and the kinetics of DM after RT. Methods: IPD for 18 RCTs were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, comprising a total of 12533 patients (6288 HRPCa & 6245 IRPCa). Multivariable Cox proportional hazards (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), DM-free survival (DMFS) & LF as a time-dependent covariate, adjusted for clinicodemographic parameters. Markov PH models, defined via transitions between 4 states, were developed to evaluate the aforementioned relationship. Proportional hazards assumption was imposed and examined for both models. Time is from randomization. Results: Median follow-up was 9.1 years. There were 795 (13%) LF & 1288 (21%) DM events for patients with HRPCa; these numbers were 449 (7%) & 451 (7%) for IRPCa. For HRPCa & IRPCa, 81% and 81% of DMs developed from a clinically relapse-free state (cRFS), with a median time of 46 and 60 months, respectively (p < 0.0001). 39% & 13% of DM events occurred within 2 years after RT for HRPCa & IRPCa, respectively. At later time points, DM events were more likely to emerge after an LF event for both HRPCa (9% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.001) and IRPCa (10% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.008). LF was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75-2.33) & DMFS (HR 1.94, 95% CI 1.75–2.15) (p < 0.01 for all) in patients with HRPCa. LF was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not OS in patients with IRPCa. Patients who had not transitioned to the LF state had a significantly lower HR of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.32, 95% CI 0.21–0.50, p < 0.001). Conclusions: LF is an independent prognosticator of OS, PCSS & DMFS in HRPCa and of DMFS in IRPCa. The predominant mode of DM development is from the cRFS state, underscoring the importance of accurate upfront staging & systemic therapy. However, particularly at late time points, an increasing proportion of DM events originated after diagnosis of a LF, constituting a “second wave” of DM events. This suggests that optimizing local control is also important, though the majority of DM events appear prior to a clinically-detected LF.
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Kyaw, Kay Thwe, Elizabeth Helzner, Carl Rosenberg, and Michael Reinhardt. "Role of Nativity in End of Life Care Planning." Innovation in Aging 5, Supplement_1 (December 1, 2021): 951. http://dx.doi.org/10.1093/geroni/igab046.3434.
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Abstract Given the rapidly aging population, optimal end-of-life (EOL) consistent with individual wishes is a public health priority. Advanced Care Planning (ACP) involves Advanced Directives (AD) and establishing a Power of Attorney (POA). AD describe EOL Care preferences including options to limit treatment, withhold treatment, provide comfort care, and prolong treatments. Nativity can provide meaningful guidance in decision-making at the end of life. Data from this study came from the Health and Retirement Study, nationally representative longitudinal study of U.S. residents. The sample included 4,015 older adults, 65 and above years of age who died during study follow-up. Nativity was categorized as U.S born and Foreign born. ACP variables included presence of AD and POA, and EOLC preferences included provide comfort care, limit, withhold, or prolong treatment. Covariates included age, gender, race, marital status, education, and subjective health at baseline. Cox Proportional Hazards (Cox PH) and Weibull Models were used to identify associations between nativity and end of life care. Results: Compared to U.S born, Foreign born participants were less likely to have POA (HR: 0.75; 95% CI:0.64-0.89) in Cox PH and POA (HR: 0.63; 95 % CI:0.53-0.75) Weibull models in unadjusted models, limited treatment (HR: 1.58; 95 % CI: 1.2, 2.1), and prolong treatment (HR: 0.23; 95 % CI:0.06-0.99) and Cox PH and (HR: 0.20; 95 % CI: 0.05-0.83) in Weibull modes. Conclusion: There are differences in Advanced Care Planning by nativity. Country of origin should be considered when helping individuals plan for end-of-life care.
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Costello, R. E., B. Birlie Yimer, M. Jani, and W. Dixon. "FRI0120 ORAL GLUCOCORTICOID USE IS ASSOCIATED WITH HYPERTENSION IN PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 641.1–641. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1000.
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Background:Oral glucocorticoids (GC) are frequently prescribed to patients with rheumatoid arthritis (RA), however GC use is associated with a number of potential side effects. Hypertension is cited as a possible side effect, but few studies have specifically investigated GC-associated hypertension in patients with RA with conflicting results.Objectives:The aim of this study was to determine whether GCs were associated with an increased risk of incident hypertension in a cohort of patients with RA.Methods:A retrospective cohort of patients with incident RA and no hypertension at RA diagnosis were identified from UK primary care electronic health records (Clinical Practice Research Datalink). GC prescriptions were used to determine time-varying GC use and dose, categorised as: no use, >0–4.9 mg/day, 5–7.4 mg/day, 7.5–14.9 mg/day, ≥15mg/day. A 3-month risk attribution model was used where patients continued to remain at risk for 3 months after the end of prescriptions. Hypertension was identified if a patient had either: 1) 2 consecutive systolic blood pressure (BP) measurements >140mmHg within a year, 2) 2 consecutive diastolic BP measurements >90mmHg within a year or 3) antihypertensive prescriptions on at least two occasions and a Read code for hypertension. Unadjusted and adjusted Cox proportional hazards (PH) regression models were fitted to determine if there was an association between GC use and hypertension. Models were adjusted for baseline age, gender, baseline body mass index, baseline ever smoking, time-varying synthetic disease-modifying anti-rheumatic drug use, time-varying non-steroidal anti-inflammatory drug use and baseline Charlson comorbidity index.Results:There were 17,760 patients with incident RA and no hypertension. The cohort had a mean age of 56.3 ± 12.7 years and were predominantly female (68%). 7,421 (42%) were prescribed GCs during follow-up. There were 6,243 cases of incident hypertension over 97547 person years (pyrs) of follow-up, giving an incident rate of 64.1 per 1000 pyrs. Of those 1321 cases were in those exposed to GCs and 4922 were in those unexposed, giving incident rates of 87.6 per 1000 pyrs and 59.7 per 1000 pyrs, respectively. The adjusted Cox PH model indicated that recent GC use was associated with a 17% increased hazard of hypertension (hazard ratio: 1.17 (95% CI 1.10 to 1.24)). When categorised by dose, the adjusted model indicated only doses above 7.5mg were significantly associated with hypertension (Table 1).Table 1.Unadjusted and adjusted Cox proportional hazards regression model resultsUnadjustedHR (95% CI)Age and gender adjustedHR (95% CI)Fully adjusted* HR (95% CI)Recent GC use1.44(1.35 to 1.53)1.23(1.16 to 1.31)1.17(1.10 to 1.24)Recent GC doseNo GC useReferenceReferenceReference>0 – 4.9mg1.35(1.21 to 1.53)1.13(1.01 to 1.28)1.10(0.98 to 1.24)5mg – 7.4mg1.40(1.22 to 1.60)1.11(0.97 to 1.27)1.07(0.93 to 1.23)7.5mg – 14.9mg1.44(1.33 to 1.57)1.26(1.16 to 1.38)1.18(1.08 to 1.29)15mg and over1.60(1.40 to 1.84)1.45(1.27 to 1.66)1.36(1.18 to 1.56)* Adjusted for: Baseline age, gender, baseline body mass index, baseline ever smoking, synthetic disease-modifying anti-rheumatic drug use (time-varying), non-steroidal anti-inflammatory drug use (time-varying) and baseline Charlson comorbidity index.Conclusion:In this large cohort of patients with RA and without hypertension, recent GC use was associated with incident hypertension. In particular doses ≥7.5mg were associated with hypertension while the association with lower doses was inconclusive. Clinicians need to consider cardiovascular risk when prescribing GCs and ensure BP is regularly monitored.Disclosure of Interests:Ruth E Costello: None declared, Belay Birlie Yimer: None declared, Meghna Jani Speakers bureau: Grifols, William Dixon Consultant of: Bayer and Google
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Singh, Pushpendra Pal, and A. K. Chopra. "Removal of Zn2+ and Pb2+ using new isolates of Bacillus spp. PPS03 and Bacillus subtilis PPS04 from Paper mill effluents using indigenously designed Bench-top Bioreactor." Journal of Applied and Natural Science 6, no. 1 (June 1, 2014): 47–56. http://dx.doi.org/10.31018/jans.v6i1.374.
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Biosorption processes have the potential to decrease environmental hazards through their factors such as initial metal ion concentration, temperature, pH and biomass concentration in the solution. In the present study biosorption process was performed using the strains of Bacillus spp. PPS 03 (KF710041) and Bacillus subtilis PPS 04 (KF710042) isolated from sediment core of Paper mill effluent (PME) for the removal of Zn2+and Pb2+ in an indigenously designed Bench-top Bioreactor. The temperature, initial pH, biomass and incubation period of PME for Zn2+ and Pb2+ reduction was standardized. The strains exhibited significant reduction in Zn2+ and Pb2+ of PME to the extent of 73.29% and 85.64% with PPS 03 and 78.15% and 87.57% respectively with PPS 04 after 120 hrs of aerobic treatment. The reduction in the metals occurred from first day of the treatment, but the maximum reduction in these metals was observed after 120 hrs. at pH (7.0±0.2), temperature (35±1.0°C) and biomass (5% v/ v) of the bacterial strains. The removal of metals with strain PPS 04 was more in comparison to the strain PPS 03. The Freundlich isotherms on the data showed that it was linearly fitted for Zn2+and Pb2+. The values of correlation coefficient (R2) of Freundlich isotherms were greater than 0.812 for Pb2+ and Zn2+. The kinetic study for the rate of removal of Pb2+ and Zn2+ by both species was found to best fit a Pseudo first order reaction. The rate constant was found to be inversely proportional to the concentration of parameters. Thus, the microbial strains were found efficient for the biosorption/removal of Pb2+ and Zn2+.
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Halabi, Susan, Andrew J. Armstrong, A. Oliver Sartor, Johann Sebastian De Bono, Ellen B. Kaplan, and Eric Jay Small. "Prostate-specific antigen decline (PSA) as a surrogate for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4515. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4515.
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4515 Background: PSA kinetics, and more specifically a 30% decline in PSA following initiation of first-line chemotherapy with docetaxel, has been reported to be a surrogate endpoint for OS in mCRPC pts. The objective of this analysis was to evaluate PSA kinetics as surrogate endpoints for overall survival (OS) in patients who were receiving second line chemotherapy following progression after docetaxel front line therapy. Methods: Data from a phase III trial of 755 mCRPC pts randomized to treatment with cabazitaxel in combination with prednisone (C+P) every 3 weeks or mitoxantrone in combination with prednisone (M+P) were used. All pts were previously treated with a docetaxel-containing regimen. PSA decline (≥30% and ≥50% ) and PSA velocity within the first three months of treatment were evaluated as potential surrogate endpoints for OS. The proportional hazards (PH) model was used to test for Prentice’s criteria and the proportion of treatment explained (PTE) was computed as a second test of surrogacy. PTE was defined as one minus the ratio of the treatment coefficient in the adjusted PH model (includes PSA decline or velocity) to the treatment coefficient in the unadjusted PH model. Results: Of 755 men, 654 had sufficient PSA data to be included in the analysis. Treatment arm (C+P vs. M+P) was prognostic of OS with a hazard ratio (HR) of 0.65 (95% CI=0.54-0.79, p<0.001). A 30% PSA decline within three months of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57, p-value<0.001) for OS. After adjusting for treatment effect, the HR for 30% PSA decline was 0.50 (95% CI= 0.40-0.62, p<0.001) but treatment arm remained statistically significant thus failing Prentice’s third criterion. The PTE for ≥30% decline in PSA within three months was 0.39 (95% CI= 0.36-0.42) indicating a lack of surrogacy for OS. Similar results were observed for pts who experienced ≥50% decline in PSA and PSA velocity. Conclusions: Neither PSA decline (≥30% and ≥50%) nor PSA velocity within the first three months of therapy are surrogate endpoints for OS in pts receiving second line chemotherapy.
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Nyasulu, Peter S., Birhanu T. Ayele, Coenraad F. Koegelenberg, Elvis Irusen, Usha Lalla, Razeen Davids, Yazied Chothia, et al. "Clinical characteristics associated with mortality of COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa." PLOS ONE 17, no. 12 (December 30, 2022): e0279565. http://dx.doi.org/10.1371/journal.pone.0279565.
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Background Over 130 million people have been diagnosed with Coronavirus disease 2019 (COVID-19), and more than one million fatalities have been reported worldwide. South Africa is unique in having a quadruple disease burden of type 2 diabetes, hypertension, human immunodeficiency virus (HIV) and tuberculosis, making COVID-19-related mortality of particular interest in the country. The aim of this study was to investigate the clinical characteristics and associated mortality of COVID-19 patients admitted to an intensive care unit (ICU) in a South African setting. Methods and findings We performed a prospective observational study of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted to the ICU of a South African tertiary hospital in Cape Town. The mortality and discharge rates were the primary outcomes. Demographic, clinical and laboratory data were analysed, and multivariable robust Poisson regression model was used to identify risk factors for mortality. Furthermore, Cox proportional hazards regression model was performed to assess the association between time to death and the predictor variables. Factors associated with death (time to death) at p-value < 0.05 were considered statistically significant. Of the 402 patients admitted to the ICU, 250 (62%) died, and another 12 (3%) died in the hospital after being discharged from the ICU. The median age of the study population was 54.1 years (IQR: 46.0–61.6). The mortality rate among those who were intubated was significantly higher at 201/221 (91%). After adjusting for confounding, multivariable robust Poisson regression analysis revealed that age more than 48 years, requiring invasive mechanical ventilation, HIV status, procalcitonin (PCT), Troponin T, Aspartate Aminotransferase (AST), and a low pH on admission all significantly predicted mortality. Three main risk factors predictive of mortality were identified in the analysis using Cox regression Cox proportional hazards regression model. HIV positive status, myalgia, and intubated in the ICU were identified as independent prognostic factors. Conclusions In this study, the mortality rate in COVID-19 patients admitted to the ICU was high. Older age, the need for invasive mechanical ventilation, HIV status, and metabolic acidosis were found to be significant predictors of mortality in patients admitted to the ICU.
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Das, Prantik, James Price, Michael Jones, Cristina Martin-Fernandez, Akram Ali, Thangrarajh Mugunthan, and Chandrani Mallick. "Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 303. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.303.
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303 Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1st February 2012 and 31st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.
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Mehari, Alem, Xin Tian, Shoaib Alam, Dihua Xu, Catherine Seamon, Mark T. Gladwin, Roberto F. Machado, and Gregory J. Kato. "Hemodynamic Parameters Predict Mortality In Sickle Cell Disease-Related Pulmonary Hypertension." Blood 116, no. 21 (November 19, 2010): 2668. http://dx.doi.org/10.1182/blood.v116.21.2668.2668.
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Abstract Abstract 2668 Background: Indirect markers of pulmonary hypertension (PH) are associated with significant risk of early mortality in adults with sickle cell disease (SCD). Currently, there are limited data on hemodynamic predictors of mortality in PH patients with SCD. Objective: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patient with SCD-related PH documented by right heart catheterization (RHC). Methods: We collected hemodynamic data from 86 consecutive adults with SCD who underwent RHC based on elevated tricuspid regurgitant velocity (TRV) on echocardiography and clinical suspicion of PH. Survival rates from the time of diagnosis of PH by RHC and dates of enrollment were estimated by the Kaplan-Meier method. Mortality risk factors were analyzed by the Cox proportional hazards regression. Patients found to have PH by RHC (mean pulmonary artery pressure ≥25 mmHg). were compared to 447 general sickle patients for hemolytic markers, TRV, exercise capacity and overall survival. For a highly stringent definition of pulmonary arterial hypertension (PAH), we utilized a highly conservative pulmonary vascular resistance (PVR) cutoff of 3 Woods' units, approximately six standard deviations (SD) above normal in adults with SCD. Pulmonary venous hypertension (PVH) was defined by pulmonary capillary wedge pressure >15 mmHg. Results: Fifty six (65%) patients from the RHC cohort had PH. The PH group had significantly higher hemolytic markers (serum lactate dehydrogenase (LDH), aspartate aminotransferase, bilirubin), higher TRV (3.3 ± 0.5 vs. 2.3 ± 0.5 m/s, mean ± SD, P<0.001), and lower six minute walk distance (358 ± 113 vs. 486 ± 88 m, P<0.001) as compared to the general sickle cell group. Further hemodynamic characterization of the PH group showed 25 (44.6%) patients with PVH, 16 (28.6 %) patients with PAH and 15 (26.8 %) patients having PH with less elevated resistance and normal PCWP characterized by very high cardiac output (mean CO=9.6 ± 2.5 L/min). During a median follow-up of 4 years, the overall mortality rate was higher in the PH group (19 deaths, 34%) than either the group without PH by RHC (3 deaths, 10%) (hazard ratio [HR] 3.55, P=0.03 ) or the general sickle cell group (50 deaths, 13%) (HR 2.49, P <0.001). Survival estimates for the PH versus without PH were 88.7% vs. 100% at 1 year; 73.2% vs. 92% at 3 years; and 61.5% vs. 84.9% at 5 years. The estimated median survival time was 6.4 years for patients with PH. Survival was not significantly different between the three PH subgroups. All three of the PH subgroups showed significantly high LDH levels: PVH (458 ± 252 IU/L, P=0.011), PAH (430 ± 189 IU/L, P=0.027), and PH with less elevated PVR/normal PCWP (525 ± 262 IU/L, P=0.002), compared to SCD controls (339 ± 151 IU/L). All three PH groups also showed functional impairment in their six minute walk distance: PVH (331 ± 116 m, P<0.001), PAH (350 ± 115 m, P<0.001), and PH with less elevated PVR/normal PCWP (416 ± 90 m, P=0.004), compared to SCD controls (486 ± 88 m). Univariate Cox regression analysis identified the following predictors of overall survival: pulmonary artery systolic pressure (HR 1.02; P=0.041), pulmonary artery diastolic pressure (HR 1.06; P=0.008), mean pulmonary artery pressure (HR 1.04; P=0.015), transpulmonary gradient (HR 1.05; P=0.014), indexed pulmonary vascular resistance (HR 1.18 each Wood's unit; P=0.005) and six minute walk distance (HR 0.60 each 100 m change; P=0.01). Conclusion: Mortality in SCD related PH is high and is directly correlated with typical indicators of PH severity, including specific hemodynamic measures and impaired exercise capacity. This suggests that PH is contributing significantly to early mortality in SCD adults. Less conservative cutoffs for PVR are accepted by many authorities in the setting of high flow, and this would result in even a higher percentage of PAH diagnoses in our analysis. Disclosures: No relevant conflicts of interest to declare.
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Lin, Emily Pei-Ying, Chih-Yuan Hsu, Pan-Chyr Yang, and Yu Shyr. "Changing paradigm in oncology clinical trials: Cox-TEL—Adjustment made ready for early crossover and tail tale." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15067-e15067. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15067.
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e15067 Background: Approvals of immune checkpoint inhibitors (ICI) were made based on positive clinical trial results analyzed by the Cox proportional hazards (PH) model. With ICI data, however, long tails and early crossover in survival curves, which violate the Cox PH assumption, can lead to misinterpretation of clinical significance of findings. Here we introduce the Cox-TEL and show the differences of study results before and after Cox-TEL adjustment using KEYNOTE 042 and 045 as examples. Methods: Cox-TEL is built on the mathematical foundation of Taylor expansion. As an easily implemented alternative of PH cure model, it not only infers associations between survival probabilities of the two study arms among patients without long-term survival (poor-responders), but also estimates differences in proportion (DP) between arms among patients in the long-tail segment of the survival curve (true-responders). Results: In KEYNOTE 042, the Cox-TEL HRs for death were statistically insignificant across all subgroups. The trend of DP, on the other hand, is positively related to that of PD-L1 TPS and inverted related to that of Cox HR when the PD-L1 ≥50% cohort is covered. In KEYNOTE 045, the Cox-TEL HRs suggested that for the poor-responders, pembrolizumab did not do better than chemotherapy in terms of overall survival (OS) and might do harm to the patients in terms of progression-free survival (PFS). For the true-responders, DPs of OS and PFS were both statistically significant (Table). Conclusions: Our data demonstrated the biases derived from insufficient data analyses and strengthened the necessity of analytic model revisits in the new oncology era of which cure for advanced cancers is no longer impossible. [Table: see text]
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Batra, Atul, Colleen Ann Cuthbert, Andrew Harper, Lin Yang, Devon J. Boyne, Rodrigo Rigo, and Winson Y. Cheung. "Impact of baseline symptom burden as assessed by patient-reported outcomes (PROs) on overall survival (OS) of patients with metastatic cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 12020. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.12020.
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12020 Background: Patients with metastatic cancer experience variable symptom burden, but serial symptom assessments using PROs may be challenging to implement in routine clinical practices. We aimed to determine if a single measurement of symptom burden at the time of metastatic diagnosis is associated with survival. Methods: We examined prospectively collected baseline PROs of patients newly diagnosed with metastatic breast, lung, colorectal, or prostate cancer using the revised Edmonton Symptom Assessment System (ESASr) questionnaire from a large province (Alberta, Canada) between 2016 and 2019. The ESASr was categorized into physical (PH), psychosocial (PS), and total symptom (TS) domains whereby scores were classified as mild (0-3), moderate (4-6), or severe (7-10). Multivariable Cox proportional hazards models were constructed to evaluate the effect of baseline symptom scores on OS. Results: We identified 1,315 patients, of whom 57% were men and median age was 66 (IQR, 27-93) years. There were 180, 601, 240, and 294 patients with breast, lung, colorectal, and prostate cancer, respectively. Approximately one-quarter of all patients reported moderate to severe PH, PS, and TS scores, with lung cancer patients experiencing the highest symptom intensity across all domains ( P<0.0001). While age did not affect symptom scores, women were more likely to report severe PH, PS, and TS scores as compared to men ( P=0.02, 0.002, and 0.007, respectively). On multivariable Cox regression analysis, older age (HR 1.02, 95% CI, 1.02-1.03, P<0.0001) and female sex (HR 1.67, 95% CI, 1.39-1.99, P<0.0001) were predictive of worse OS as were severe baseline PH and TS scores (see Table) . However, baseline PS scores were not related to OS. Conclusions: A single assessment of baseline symptom burden using the ESASr in patients with metastatic cancer has significant prognostic value. This may represent a feasible first step toward routine collection of PROs in real-world settings where serial symptom measurements can be challenging to implement. [Table: see text]
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Raboud, Janet, Sandra Blitz, Tony Antoniou, Mona Loutfy, and Sharon Walmsley. "Recent Immigrants Show improved Clinical Outcomes at a Tertiary Care HIV Clinic." Canadian Journal of Infectious Diseases and Medical Microbiology 23, no. 1 (2012): 9–14. http://dx.doi.org/10.1155/2012/963474.
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BACKGROUND: In recent years, the proportion of patients attending tertiary care HIV clinics who are recent immigrants to Canada has increased dramatically.METHODS: Among patients first seen at the Toronto Hospital Immunodeficiency Clinic (Toronto, Ontario) between January 1, 2000 and August 31, 2009, the time to death from the first positive HIV test was compared between individuals who had immigrated to Canada within 10 years of their first visit and individuals who were either Canadian-born or who had immigrated more than 10 years before their first clinic visit. In addition, for the antiretroviral-naive patients in these two groups who initiated combination antiretroviral therapy, the time to and the duration of virologic suppression were compared.RESULTS: In a multivariable proportional hazards (PH) model, recent immigrant status was associated with decreased mortality (HR 0.11, P=0.03) after adjusting for age, CD4 count and the risk factor for men having sex with men. In multivariable PH models, recent female immigrants achieved virologic suppression more quickly (HR 1.51, P=0.02), while male immigrants (HR 1.14, P=0.44) and female nonimmigrants (HR 0.90, P=0.61) had similar times to virologic suppression as male nonimmigrants, respectively, after adjusting for the year of and viral load at combination antiretroviral therapy initiation. When pregnant women were removed from the analysis, there were no significant differences in the rates of virologic rebound according to sex or immigration status.DISCUSSION: Despite the perceived barriers of newcomers to Canada, mortality was lower among recent immigrants and virologic suppression was achieved more quickly in recent female immigrants.
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Nater, A., LA Tetreault, B. Kopjar, PM Arnold, MB Dekutoski, JA Finkelstein, CG Fisher, et al. "C.02 Predictors of survival in a surgical series of Metastatic Spinal Cord Compression and a complete external validation of 8 models in a prospective multi-centre study." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S14. http://dx.doi.org/10.1017/cjn.2018.97.
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Background: We aimed to identify preoperative predictors of survival in Metastatic Epidural Spinal Cord Compression (MESCC) patients surgically treated, examine how these predictors relate to eight prognostic models, and to perform the first full external validation of these models in accordance with the TRIPOD statement. Methods: 142 surgically treated MESCC patients were enrolled in a prospective, multicenter cohort study and followed for 12 months or until death. Cox proportional hazards (PH) regressions were used. Non-collinear predictors with <10% missing data, ≥10 events per stratum and p<0.05 in univariable analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi, Tomita, modified Bauer, van der Linden, Bartels, OSRI, Bartels and Bollen, we examined calibration and discrimination; survival stratified by risk groups with the Kaplan-Meier method and log-rank test. Results: Primary tumor, organ metastasis and SF-36v2 PC were associated with survival in multivariable analysis; corrected discrimination was 0.68. These three predictors were common to most current prognostic models. However, calibration was poor overall while discrimation was possibly helpful. Conclusions: Primary tumor type (breast, prostate and thyroid), absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival in surgical MESCC patients. Clinicians should use these 8 prognostic models with caution.
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Gladwin, Mark T., Robyn J. Barst, J. Simon R. Gibbs, Marianna Hildesheim, Vandana Sachdev, Mehdi Nouraie, Kathryn L. Hassell, et al. "Risk Factors for Death in 632 Patients with Sickle Cell Anemia in the United States and United Kingdom." Blood 120, no. 21 (November 16, 2012): 3240. http://dx.doi.org/10.1182/blood.v120.21.3240.3240.
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Abstract Abstract 3240 The role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods: Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results: Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV < 3.0 m/sec (p<0.0001). The unadjusted hazard ratios for death were 11.14 (95% CI 4.1–30.1; p<0.0001) for patients with TRV above and below 3.0 m/sec and 4.55 (95% CI 1.8–11.3; p=0.001) for patients with NT-proBNP above and below 160 pg/mL. For patients with both high TRV (≥ 3.0 m/sec) and high NT-proBNP (≥ 160 pg/mL), the unadjusted hazard ratio was 14.86 (95% CI 5.5–39.9; p<0.0001). Overall, an increased risk of death was observed for both age and gender, with males at higher risk relative to females (HR=2.48, 95% CI 1.0–6.1; p=0.05), and patients older than 47 years (HR=2.02, 95% CI 1.1–3.8; p=0.03). Associations with mortality were also observed for chronic transfusions (HR=3.00, 95% CI 1.2–7.8; p=0.02) and a NYHA/WHO class value or III or IV (HR=4.52, 95% CI 1.4–14.3; p=0.01). Other variables associated with mortality in our cohort included a high hemolytic component, aspartate aminotransferase (AST), ferritin, and creatinine. Variables not associated with mortality included current hydroxyurea use, SC disease, self-reported history of painful episodes, and six-minute walk distance. In stepwise multiple proportional hazards regression analysis, the association between TRV and mortality remained significant after adjustment for all other risk factors, including ferritin, AST, creatinine and even NT-proBNP (HR 4.27, 95%CI 1.3–14.1; p=0.04). Conclusions: Using a more conservative cut-off value of TRV ≥ 3.0 m/sec as defining PH in a large screening population of sickle cell disease patients, PH occurs in approximately 10% of unselected screened patients and is associated with the highest unadjusted and adjusted risk for death of any measured variable. Disclosures: Gladwin: Bayer Corp: Consultancy, Research Funding; NIH and NHLBI: Research Funding; Gilead Sciences: Research Funding. Barst:Ventripoint: Stock options Other; Actelion, Eli Lilly, Gilead, Glaxo Smith-Kline (GSK), Medtronics, Bayer, Ikaria, Pfizer, Novartis, VentriPoint: Consultancy, Honoraria. Girgis:NIH/NHLBI: Research Funding, Travel support Other. Rosenzweig:NIH: Research Funding. Badesch:NIH: Research Funding. Lanzkron:NIH: Research Funding.
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Fung, Andrea S., Karen Kopciuk, Michelle L. Dean, Adrijana D’Silva, Shannon Otsuka, Alexander Klimowicz, Desiree Hao, Don Morris, and D. Gwyn Bebb. "CXCR4 expression in lung carcinogenesis: Evaluating gender-specific differences in survival outcomes based on CXCR4 expression in early stage non-small cell lung cancer patients." PLOS ONE 16, no. 1 (January 28, 2021): e0241240. http://dx.doi.org/10.1371/journal.pone.0241240.
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Introduction Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. Methods Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003–2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). Results 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. Conclusions CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.
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Cullen, Jennifer, Yongmei Chen, Huai-Ching Kuo, Kevin R. Rice, Inger L. Rosner, and Jonathan Forsberg. "Modeling time from bone metastasis to death in a racially diverse cohort of military health care beneficiaries." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 246. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.246.
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246 Background: Development of prostate cancer (PCa) metastasis, while uncommonly observed in US men, typically occurs to bone and ultimately leads to disease-specific death. The goal of this study was to estimate OS in a racially diverse cohort of military health care beneficiaries diagnosed with metastatic PCa to bone, to enhance understanding of factors such as patient race and receipt of palliative treatment, that potentially affect OS in advanced PCa patients. Methods: A retrospective cohort study was conducted, examining men consented to participate in the CPDR multi-center national database who underwent biopsy for suspicion of prostate cancer between 1989-2017 and subsequently diagnosed with bone metastasis, confirmed by bone scan, bone biopsy and/or MRI. Multivariable Cox proportional hazards (PH) analysis was used to model OS as a function of race and palliative treatment, controlling for clinical covariates. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: Among 17,356 patients diagnosed with prostate cancer (PCa) between 1989 and 2017, 869 (5.0%) developed bone metastasis. Median patient age was 67 years; median follow-up time following diagnosis with bone metastasis was 2.4 years. Over one-fifth of patients (22.5%) self-reported as African American. Only 11.5% of all patients with metastasis received palliative treatment (radiation (RT) only, RT+ hormone therapy (HT), RT+HT, or RT+HT+chemotherapy). While race did not predict OS, receipt of palliative treatment was strongly predictive of better OS (p<0.0005). Conclusions: Patient race did not predict OS among those with distant metastatic PCa but receipt of palliative care and slower PSADT were critical factors in lengthening OS. This work is being extended to examine the combinations and sequencing of palliative care on OS, to provide improved patient-tailored prediction tools for men with advanced prostate cancer. [Table: see text]