survPresmooth: An R Package for Presmoothed Estimation in Survival Analysis

The survPresmooth package for R implements nonparametric presmoothed estimators of the main functions studied in survival analysis (survival, density, hazard and cumulative hazard functions). Presmoothed versions of the classical nonparametric estimators have been shown to increase efficiency if the presmoothing bandwidth is suitably chosen. The survPresmooth package provides plug-in and bootstrap bandwidth selectors, also allowing the possibility of using fixed bandwidths

npcure: An R Package for Nonparametric Inference in Mixture Cure Models

[Abstract] Mixture cure models have been widely used to analyze survival data with a cure fraction. They assume that a subgroup of the individuals under study will never experience the event (cured subjects). So, the goal is twofold: to study both the cure probability and the failure time of the uncured individuals through a proper survival function (latency). The R package npcure implements a completely nonparametric approach for estimating these functions in mixture cure models, considering right-censored survival times. Nonparametric estimators for the cure probability and the latency as functions of a covariate are provided. Bootstrap bandwidth selectors for the estimators are included. The package also implements a nonparametric covariate significance test for the cure probability, which can be applied with a continuous, discrete, or qualitative covariate. © 2021. All Rights Reserved.The first author’s research was sponsored by the Beatriz Galindo Junior Spanish Grant from Ministerio de Ciencia, Innovación y Universidades (MICINN) with reference BGP18/00154. All the authors acknowledge partial support by the MICINN Grant MTM2017-82724-R (EU ERDF support included), and by Xunta de Galicia (Centro Singular de Investigación de Galicia accreditation ED431G/01 2016-2019 and Grupos de Referencia Competitiva CN2012/130 and ED431C2016-015) and the European Union (European Regional Development Fund - ERDF)Xunta de Galicia; ED431G/01 2016-2019Xunta de Galicia; CN2012/130Xunta de Galicia; ED431C2016-01

A Product-Limit Estimator of the Conditional Survival Function When Cure Status Is Partially Known

This is the peer reviewed version of the following article: Safari, W. C., López-de-Ullibarri, I., & Jácome, M. A. (2021). Correction: A product-limit estimator of the conditional survival function when cure status is partially known. Biometrical Journal, 63, 1544–1546. https://doi.org/10.1002/bimj.202000173, which has been published in final form at https://doi.org/10.1002/bimj.202000173. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.[Abstract] We introduce a nonparametric estimator of the conditional survival function in the mixture cure model for right-censored data when cure status is partially known. The estimator is developed for the setting of a single continuous covariate but it can be extended to multiple covariates. It extends the estimator of Beran, which ignores cure status information. We obtain an almost sure representation, from which the strong consistency and asymptotic normality of the estimator are derived. Asymptotic expressions of the bias and variance demonstrate a reduction in the variance with respect to Beran's estimator. A simulation study shows that, if the bandwidth parameter is suitably chosen, our estimator performs better than others for an ample range of covariate values. A bootstrap bandwidth selector is proposed. Finally, the proposed estimator is applied to a real dataset studying survival of sarcoma patients.We are grateful to Dr. Ángel Díaz-Lagares, Head of Cancer Epigenomics Lab, Translational Medical Oncology Group (IDIS, CHUS), for providing with the sarcoma dataset obtained from the public The Cancer Genome Atlas (TCGA) program. This work has been supported by MINECO grant MTM2017-82724-R, the Xunta de Galicia (Grupos de Referencia Competitiva ED431C-2016-015), and the Centro de Investigación de Galicia “CITIC,” funded by Xunta de Galicia and the European Union (European Regional Development Fund-Galicia 2014-2020 Program), by grant ED431G 2019/01, all of them through the ERDFXunta de Galicia; ED431C-2016-015Xunta de Galicia; ED431G 2019/0

Nonparametric Kernel Estimation of the Probability of Cure in a Mixture Cure Model when the Cure Status is Partially Observed

[Abstract] Cure models are a class of time-to-event models where a proportion of individuals will never experience the event of interest. The lifetimes of these so-called cured individuals are always censored. It is usually assumed that one never knows which censored observation is cured and which is uncured, so the cure status is unknown for censored times. In this paper, we develop a method to estimate the probability of cure in the mixture cure model when some censored individuals are known to be cured. A cure probability estimator that incorporates the cure status information is introduced. This estimator is shown to be strongly consistent and asymptotically normally distributed. Two alternative estimators are also presented. The first one considers a competing risks approach with two types of competing events, the event of interest and the cure. The second alternative estimator is based on the fact that the probability of cure can be written as the conditional mean of the cure status. Hence, nonparametric regression methods can be applied to estimate this conditional mean. However, the cure status remains unknown for some censored individuals. Consequently, the application of regression methods in this context requires handling missing data in the response variable (cure status). Simulations are performed to evaluate the finite sample performance of the estimators, and we apply them to the analysis of two datasets related to survival of breast cancer patients and length of hospital stay of COVID-19 patients requiring intensive care.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research/work has been supported by MICINN grant PID2020-113578RB-I00, and by the Xunta de Galicia (Grupos de Referencia Competitiva ED431C-2020/14 and Centro de Investigación del Sistema universitario de Galicia ED431G 2019/01), all of them through the ERDFXunta de Galicia; ED431C-2020/14Xunta de Galicia; ED431G 2019/0

Nonparametric Inference for Mixture Cure Model When Cure Information Is Partially Available

Presented at the 4th XoveTIC Conference, A Coruña, Spain, 7–8 October 2021.[Abstract] We introduce nonparametric estimators to estimate the conditional survival function, cure probability and latency function in the setting of a mixture cure model when the cure status is partially known. For the sake of illustration, we present an application concerning patients hospitalized with COVID-19 in Galicia (Spain) during the first outbreak of the epidemic.This work has been supported by MINECO grant MTM2017-82724-R and the Xunta de Galicia (Grupos de Referencia Competitiva ED431C-2016-014) and we wish to acknowledge the support received from the Centro de Investigación de Galicia “CITIC” funded by Xunta de Galicia and the European Union (European Regional Development Fund Galicia 2014–2020 Program) by grant ED431G 2019/01Xunta de Galicia; ED431C-2016-014Xunta de Galicia; ED431G 2019/0

Validation of a questionnaire of knowledge and attitudes about the subcutaneous venous reservoir in nursing

[Abstract] Objective: design and validate a questionnaire to evaluate the knowledge and attitudes of nurses about the subcutaneous venous reservoir. Method: pilot test: 30 specialized care nurses. Main study: 236 nurses of primary and specialized care. Content validity was evaluated by Lawshe index, reliability by test-retest, internal consistency by Cronbach alpha, and construct validity by exploratory factorial analysis. Results: Items with a Lawshe index lower than 0.51 were eliminated. In the test-retest, the intraclass correlation coefficient was higher than 0.75 for all items. The Cronbach alpha of the attitude questionnaire reached 0.865. The Cronbach alpha value for knowledge was 0.750. The exploratory factor analysis identified a set of four dimensions for each part that explain 64% (attitude) to 80% (knowledge) of variability. Conclusion: the analysis of the reliability and validity of the questionnaire supports its use as an instrument to assess the knowledge and attitudes of nurses towards the subcutaneous venous reservoir.Ministerio de Asuntos Económicos y Transformación Digital (España); MTM2014-52876-RMinisterio de Asuntos Económicos y Transformación Digital (España); MTM2017-82724-RXunta de Galicia; ED431C-2016-015Xunta de Galicia; ED431C-2018/38Xunta de Galicia; ED431G / 0

Efecto de un programa de formación en atención primaria sobre la optimización del tratamiento con bloqueadores beta en pacientes ancianos con insuficiencia cardiaca

[Abstract] Introduction and objectives. Underuse of beta-blockers may contribute to elevated mortality in chronic heart failure. The aim of this study was to determine whether a specific interventional training program for primary care physicians would help optimize the use of beta-blockers in elderly chronic heart failure patients. Methods. This randomized comparative study included 627 patients aged 70 years or more who were discharged consecutively from 53 Spanish hospitals with a principal diagnosis of chronic heart failure. In total, 292 health-care centers in the catchment areas of these hospitals were randomly assigned to two groups: one group of 146 centers carried out an interventional training program on beta-blocker use for primary care physicians belonging to the centers assigned to training, and 146 centers served as a control group. The main outcome variable was the percentage of patients who were receiving a beta-blocker at the maximum or maximum tolerated dose 3 months after hospital discharge. Results. The patients’ mean age was 78±5 years and 42% were women. There was no difference between the groups in demographic characteristics, clinical care, or treatment at discharge. The percentage of patients who received beta-blockers at the maximum tolerated dose 3 months after discharge was greater in the training group (49% vs. 38%; P=.014). Being treated in the training group was an independent predictor of receiving a beta-blocker at the MTD (odds ratio=2.46; 95% confidence interval, 1.29-4.69; P<.001). Conclusions. Implementation of an interventional training program on beta-blocker treatment for primary care physicians improved the use of these medications in elderly chronic heart failure patients.[Resumen] Introducción y objetivos. La infrautilización de bloqueadores beta puede influir en la elevada mortalidad de la insuficiencia cardiaca. El objetivo de nuestro estudio es evaluar si un programa específico de intervención sobre médicos de atención primaria permite optimizar el uso de bloqueadores beta en pacientes ancianos con insuficiencia cardiaca. Métodos. Se diseñó un estudio aleatorizado y comparativo en el que se incluyó a 627 pacientes de 70 o más años, dados de alta de forma consecutiva con el diagnóstico principal de insuficiencia cardiaca en 53 hospitales españoles. Se realizó una asignación aleatoria de los 292 centros de salud de las áreas de esos hospitales a dos grupos (formación, 146 centros, y control, 146 centros), para impartir un programa de intervención y formación sobre bloqueadores beta a los médicos pertenecientes a los centros del grupo formación. La variable principal fue el porcentaje de pacientes que recibían la dosis máxima o máxima tolerada de bloqueadores beta a los 3 meses del alta. Resultados. La edad de los pacientes era de 78 ± 5 años; el 42% eran mujeres. No hubo diferencias entre ambos grupos en sus características demográficas, clínicas o en el tratamiento al alta. El porcentaje de pacientes que recibían la dosis máxima tolerada de bloqueadores beta a los 3 meses del alta fue mayor en el grupo formación (el 49 frente al 38%; p = 0,014); pertenecer al grupo formación fue predictor independiente de recibir la dosis máxima tolerada de bloqueadores beta (odds ratio = 2,46; intervalo de confianza del 95%, 1,29-4,69; p < 0,001). Conclusiones. Un programa de formación sobre bloqueadores beta en atención primaria mejora su uso en pacientes ancianos con insuficiencia cardiaca

Diferencias en el pronóstico de la insuficiencia cardiaca con función sistólica conservada o deprimida en pacientes mayores de 70 años que toman bloqueadores beta

[Abstract] Introduction and objectives. Most studies have shown that prognosis of heart failure with preserved systolic function is as poor as that of heart failure with depressed systolic function, although these results may be biased by the fact that these types of heart failure have different characteristics (age, comorbidity, treatment), which can influence prognosis. Our aim was to determine whether short-term morbidity and mortality differed in these 2 subgroups of heart failure patients when they were comparable in terms of age, associated comorbidity, and therapy. Methods. We analyzed 2 groups of patients aged >70 years who were candidates to receive beta blockers (preserved systolic function, 245; depressed systolic function, 374), consecutively discharged from 53 participating Spanish hospitals with a diagnosis of heart failure, and compared cardiovascular morbidity and mortality 3 months after discharge. Results. Mean age was similar (77.5 ± 4.8 vs 78.2 ± 5.5 years). Left ventricular ejection fraction was 56.2% ± 8.1% vs 33% ± 6.9% (P<.001). The combined event rate (death, hospitalization for heart failure, acute coronary syndrome, or stroke) at 3 months after discharge was lower in patients with heart failure and preserved systolic function (13.4% vs 20.6%; P=.026). Depressed systolic function was an independent predictor of greater incidence of events (odds ratio=1.732; P=.048). Conclusions. In patients of similar age and receiving similar treatment, short-term prognosis is better in patients with heart failure and preserved systolic function than in those with depressed systolic function.[Resumen] Introducción y objetivos. La mayoría de los trabajos han puesto de manifiesto que el pronóstico de la insuficiencia cardiaca con función sistólica conservada es tan malo como el de la insuficiencia cardiaca con función sistólica deprimida, aunque estos resultados pueden estar sesgados debido a que estos dos tipos de insuficiencia cardiaca tienen características distintas (edad, comorbilidades, tratamiento) que pueden influir en el pronóstico. Nuestro objetivo es evaluar si la morbimortalidad a corto plazo es distinta en estos dos subgrupos de insuficiencia cardiaca, con pacientes homogéneos en cuanto a edad, comorbilidad y tratamiento recibido. Métodos. Analizamos dos grupos de pacientes mayores de 70 años y que pudieran recibir bloqueadores beta, dados de alta consecutivamente tras un ingreso por insuficiencia cardiaca en 53 hospitales españoles (función sistólica deprimida, 245; función sistólica conservada, 374), y se comparó la morbimortalidad cardiovascular a los 3 meses del alta. Resultados. Las medias de edad fueron similares (77,5 ± 4,8 frente a 78,2 ± 5,5 años). La fracción de eyección ventricular izquierda fue de 56,2 ± 8,1% frente a 33 ± 6,9% (p < 0,001). La incidencia del evento combinado (muerte, ingreso por insuficiencia cardiaca, síndrome coronario agudo o ictus) a los 3 meses del alta fue menor en los pacientes con insuficiencia cardiaca y función sistólica conservada (el 13,4 frente al 20,6%; p = 0,026). Tener la función sistólica deprimida fue predictor independiente de mayor incidencia de eventos (odds ratio = 1,732; p = 0,048). Conclusiones. En pacientes de edad similar que reciben el mismo tratamiento, el pronóstico a corto plazo es mejor en los pacientes con insuficiencia cardiaca y función sistólica conservada que en aquellos con función sistólica deprimida

Wastewater early warning system for SARS-CoV-2 outbreaks and variants in a Coruña, Spain

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract]: Wastewater-based epidemiology has been widely used as a cost-effective method for tracking the COVID-19 pandemic at the community level. Here we describe COVIDBENS, a wastewater surveillance program running from June 2020 to March 2022 in the wastewater treatment plant of Bens in A Coruña (Spain). The main goal of this work was to provide an effective early warning tool based in wastewater epidemiology to help in decision-making at both the social and public health levels. RT-qPCR procedures and Illumina sequencing were used to weekly monitor the viral load and to detect SARS-CoV-2 mutations in wastewater, respectively. In addition, own statistical models were applied to estimate the real number of infected people and the frequency of each emerging variant circulating in the community, which considerable improved the surveillance strategy. Our analysis detected 6 viral load waves in A Coruña with concentrations between 103 and 106 SARS-CoV-2 RNA copies/L. Our system was able to anticipate community outbreaks during the pandemic with 8-36 days in advance with respect to clinical reports and, to detect the emergence of new SARS-CoV-2 variants in A Coruña such as Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (B.1.1.529 and BA.2) in wastewater with 42, 30, and 27 days, respectively, before the health system did. Data generated here helped local authorities and health managers to give a faster and more efficient response to the pandemic situation, and also allowed important industrial companies to adapt their production to each situation. The wastewater-based epidemiology program developed in our metropolitan area of A Coruña (Spain) during the SARS-CoV-2 pandemic served as a powerful early warning system combining statistical models with mutations and viral load monitoring in wastewater over time.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding for open access charge: Universidade da Coruña/CISUG. This work was supported by EDAR Bens S.A., A Coruña, Spain [grant references INV04020, INV12120, INV05921, and INV148721 to MP], by the National Plan for Scientific Research, Development and Technological Innovation funded by the Institute of Health Carlos III (ISCIII), Spain—General Subdirection of Assessment and Promotion of the Research-European Regional Development Fund (FEDER) “A way of making Europe” [grant references PI15/00860 to GB, PI17/01482, and PI20/00413 to MP], by the Galician Innovation Agency (GAIN) (Xunta de Galicia, Spain) [grant references IN607A 2016/22 to GB, ED431C-2016/015 and ED431C-2020/14 to RC, ED431C 2021/53 to SL and ED431G 2019/01 and COV20/00604 to RC and SL, by Ministry of Economic Affairs and Digital Transformation (MINECO), Spain [grant references MTM2017-82724-R to RC], by the Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0006 to GB], by the “Innova Saúde” Program, (INNOVAMICROLAB project) co-founded by the Galician Healthcare Service (SERGAS) and the Spanish Ministry of Science and Innovation, and by the Spanish Network of Research in Infectious Diseases (CIBERINFEC, ISCIII), and by the European Virus Archive Global (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 871029. SR-F was financially supported by REIPI RD16/0016/006, KC-P by IN607A 2016/22 and the Spanish Association against Cancer (AECC) and JAV by IN607A 2016/22. DP was funded by grant EPICOVIGAL FONDO SUPERA-COVID19 from Banco Santander-CSIC-CRUE, Spain, and grant CT850A-2 from (Health Knowledge Agency) ACIS SERGAS from the Consellería de Sanidade of Xunta de Galicia, Spain.EDAR Bens S.A.; INV04020EDAR Bens S.A.; INV12120EDAR Bens S.A.; INV05921EDAR Bens S.A.; INV148721Xunta de Galicia; IN607A 2016/22Xunta de Galicia; ED431C-2016/015Xunta de Galicia; ED431C-2020/14Xunta de Galicia; ED431C 2021/53Xunta de Galicia; ED431G 2019/01Xunta de Galicia; COV20/0060

Bandwidth selection in kernel distribution function estimation

I present a new command, kcdf, for bandwidth selection in kernel estimation of the cumulative distribution function. I briefly review plug-in and cross-validation bandwidth selectors, both of which are implemented in kcdf. I then describe the command syntax and illustrate its use with an application to artificial data