Validación interna de modelos predictivos de regresión logística. Comando Validation (Stata)

El desarrollo de modelos predictivos de regresión logística es uno de los métodos estadísticos más empleados en el área de la medicina. La probabilidad estimada a partir de estos modelos se emplea en dos contextos distintos: pronóstico, en el cual se desea determinar la probabilidad de que un evento específico ocurrirá en el futuro; y diagnóstico, donde el objetivo se centra en la probabilidad de que cierta condición o enfermedad esté presente. Pero antes de que un modelo predictivo sea implementado en la práctica clínica debe ser validado interna y externamente. La declaración TRIPOD, recomendaciones basadas en la evidencia para el reporte de estudios de modelos predictivos, sugiere que las técnicas de validación interna tienen que ser reportadas. A pesar de ello, varias revisiones sistemáticas han demostrado que la validación interna y externa de los modelos predictivos es poco frecuente. Con el objetivo de aumentar la frecuencia de validación en los modelos predictivos en este trabajo se exponen las diferentes técnicas de validación interna: aparente, por división de datos, cruzada y bootstrap; y se ha desarrollado una herramienta sencilla, el comando validation, en el programa Stata para realizar la validación interna de un modelo predictivo mediante técnicas bootstrap. El comando validation permite evaluar los dos aspectos principales del rendimiento de un modelo predictivo: la discriminación y la calibración. La capacidad discriminante del modelo es evaluada mediante el C-Statistic aparente y ajustado por el optimismo. El rendimiento en términos de calibración se reporta mediante el test de HosmerLemeshow y la pendiente de calibración o Shrinkage factor. El comando incluye una opción gráfica que permite obtener la curva ROC, los histogramas de probabilidades predichas por el modelo en función del evento de interés y un gráfico de calibración con las probabilidades predichas vs. las observadas separadas por grupos de riesgo. Como complemento el comando reporta el número de veces que cada predictor es incluido en el modelo final en las muestras bootstrap. Este comando permitirá a los investigadores realizar de una forma sencilla la validación interna de los modelos predictivos de regresión logística empleando técnicas bootstrap

Investigación clínico-epidemiológica en pronóstico: desarrollos metodológicos y aplicación clínica

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina Preventiva y Salud Pública y Microbiología. Fecha de Lectura: 13-07-2021Esta tesis tiene embargado el acceso al texto completo hasta el 13-01-2023En esta Tesis se presentan dos modelos pronósticos para predecir desenlaces importantes en dos contextos clínicos distintos. Ambos modelos han sido desarrollados siguiendo alternativas metodológicas complementarias. En el primero de ellos, ante la ausencia en la literatura científica de herramientas que permitieran predecir el riesgo de crisis epilépticas durante el embarazo en mujeres en tratamiento antiepiléptico, se desarrolló un modelo pronóstico de novo a partir de los datos primarios recogidos en el estudio EMPiRE. En el segundo contexto clínico, la situación es distinta y se disponía ya de varios modelos en la literatura para predecir el riesgo de mortalidad postoperatoria en pacientes con endocarditis infecciosa. Por ello se optó por hacer una revisión sistemática y meta-análisis para identificar y evaluar la calidad de los modelos disponibles y, a partir de ellos, crear un modelo único (metamodelo) que fue optimizado para el registro nacional GAMES de endocarditis infecciosa. En ambos escenarios clínicos, se ha pretendido adicionalmente promover la utilización de estos modelos en la práctica clínica. Para este fin se han creado dos calculadoras online de libre acceso que han sido implementadas en la plataforma web Evidencio (https://www.evidencio.com/). Esta implementación facilita enormemente la obtención de una predicción personalizada del riesgo de los desenlaces considerados dadas las características individuales de los pacientes. A pesar de que los métodos para el desarrollo y validación de los modelos pronóstico han sido descritos por múltiples autores, estos métodos son en ocasiones complejos para investigadores con conocimientos limitados de estadística. Por ello, es recomendable que el equipo investigador de un estudio de desarrollo o validación de un modelo pronóstico cuente entre sus miembros con algún estadístico o persona con amplio bagaje metodológico. Sin embargo, no siempre es así, por lo que facilitar a los investigadores herramientas útiles y de manejo sencillo, como el comando – bsvalidation – para el software Stata que se ha presentado en el tercer estudio de la tesis, puede ayudar a paliar los efectos de las carencias metodológicas del equipo investigador

Physician-Related Variability in the Outcomes of an Invasive Treatment for Neck and Back Pain: A Multi-Level Analysis of Data Gathered in Routine Clinical Practice

[EN] Neuro-reflexotherapy (NRT) is a proven effective, invasive treatment for neck and back pain. To assess physician-related variability in results, data from post-implementation surveillance of 9023 patients treated within the Spanish National Health Service by 12 physicians were analyzed. Separate multi-level logistic regression models were developed for spinal pain (SP), referred pain (RP), and disability. The models included all patient-related variables predicting response to NRT and physician-related variables. The Intraclass Correlation Coefficient (ICC) and the Median Odds Ratio (MOR) were calculated. Adjusted MOR (95% CI) was 1.70 (1.47; 2.09) for SP, 1.60 (1.38; 1.99) for RP, and 1.65 (1.42; 2.03) for disability. Adjusted ICC (95%CI) values were 0.08 (0.05; 0.15) for SP, 0.07 (0.03; 0.14) for RP, and 0.08 (0.04; 0.14) for disability. In the sensitivity analysis, in which the 6920 patients treated during the physicians’ training period were excluded, adjusted MOR was 1.38 (1.17; 1.98) for SP, 1.37 (1.12; 2.31) for RP, and 1.25 (1.09; 1.79) for disability, while ICCs were 0.03 (0.01; 0.14) for SP, 0.03 (0.00; 0.19) for RP, and 0.02 (0.00; 0.10) for disability. In conclusion, the variability in results obtained by different NRT-certified specialists is reasonable. This suggests that current training standards are appropriateS

Predicting the evolution of neck pain episodes in routine clinical practice

[EN] Background: The objective of this study was to develop models for predicting the evolution of a neck pain (NP) episode. Methods: Three thousand two hundred twenty-five acute and chronic patients seeking care for NP, were recruited consecutively in 47 health care centers. Data on 37 variables were gathered, including gender, age, employment status, duration of pain, intensity of NP and pain referred down to the arm (AP), disability, history of neck surgery, diagnostic procedures undertaken, imaging findings, clinical diagnosis, and treatments used. Three separate multivariable logistic regression models were developed for predicting a clinically relevant improvement in NP, AP and disability at 3 months. Results: Three thousand one (93.5%%) patients attended follow-up. For all the models calibration was good. The area under the ROC curve was ≥0.717 for pain and 0.664 for disability. Factors associated with a better prognosis were: a) For all the outcomes: pain being acute (vs. chronic) and having received neuro-reflexotherapy. b) For NP: nonspecific pain (vs. pain caused by disc herniation or spinal stenosis), no signs of disc degeneration on imaging, staying at work, and being female. c) For AP: nonspecific NP and no signs of disc degeneration on imaging. d) For disability: staying at work and no signs of facet joint degeneration on imaging. Conclusions: A prospective registry can be used for developing valid predictive models to quantify the odds that a given patient with NP will experience a clinically relevant improvementSIThis study was funded by the Spanish Back Pain Research Network (REIDE), a Spanish not-for-profit organization which specializes in neck and back pain research. REIDE is funded by: a) The Kovacs Back pain Unit in the Hospital Universitario HLA-Moncloa, a private organization specializing in neck and back pain, dedicated to medical research, health care and promotion of public health, with no links to the health industry b) Fundación ASISA, a Spanish non-profit institution linked to a health insurance company (ASISA) owned by a physician’s cooperativ

Telemonitoring and home hospitalization in patients with chronic obstructive pulmonary disease: study TELEPOC.

Background: Chronic obstructive pulmonary disease (COPD) is a major consumer of healthcare resources, with most costs related to disease exacerbations. Telemonitoring of patients with COPD may help to reduce the number of exacerbations and/or the related costs. On the other hand, home hospitalization is a cost-saving alternative to inpatient hospitalization associated with increased comfort 15 for patients. The results are reported regarding using telemonitoring and home hospitalization for the management of patients with COPD. Methods: Twenty-eight patients monitored their health parameters at home for six months. A nurse remotely revised the collected parameters and followed the patients as programmed. A home care unit was dispatched to the patients’ home if an alarm signal was detected. The outcomes were compared to 20 historical data from the same patients. Results: The number of COPD exacerbations during the study period did not reduce but the number of hospital admissions decreased by 60% and the number of emergency room visits by 38%. On average, costs related to utilization of healthcare resources were reduced by €1,860.80 per patient per year. Conclusions: Telemonitoring of patients with COPD combined with home hospitalization may allow for AQ425 a reduction in healthcare costs, although its usefulness in preventing exacerbations is still unclearpre-print664 K

A Comprehensive Study of Vesicular and Non-Vesicular miRNAs from a Volume of Cerebrospinal Fluid Compatible with Clinical Practice

Cerebrospinal fluid (CSF) microRNAs (miRNAs) have emerged as potential biomarkers for minimally invasive diagnosis of central nervous system malignancies. However, despite significant advances in recent years, this field still suffers from poor data reproducibility. This is especially true in cases of infants, considered a new subject group. Implementing efficient methods to study miRNAs from clinically realistic CSF volumes is necessary for the identification of new biomarkers. Methods: We compared six protocols for characterizing miRNAs, using 200-mu L CSF from infants (aged 0-7). Four of the methods employed extracellular vesicle (EV) enrichment step and the other two obtained the miRNAs directly from cleared CSF. The efficiency of each method was assessed using real-time PCR and small RNA sequencing. We also determined the distribution of miRNAs among different CSF shuttles, using size-exclusion chromatography. Results: We identified 281 CSF miRNAs from infants. We demonstrated that the miRNAs could be efficiently detected using only 200 mu L of biofluid in case of at least two of the six methods. In the exosomal fraction, we found 12 miRNAs that might be involved in neurodevelopment. Conclusion: The Norgen and Invitrogen protocols appear suitable for the analysis of a large number of miRNAs using small CSF samples.This work was supported by the Basque Government [IT989-16], the Spanish Ministry of Economy and Competitiveness MINECO [SAF2015066312], and the Ramon Areces Foundation [FRA-17-JMF]. We thank MINECO for the REDIEX (Spanish Excellence Network in Exosomes) and the Severo Ochoa Excellence Accreditation (SEV-2016-0644). Funding for open access charge: Severo Ochoa Excellence Accreditation (SEV-2016-0644)

Sex as a prognostic factor for mortality in critically ill adults with sepsis: a systematic review and meta-analysis.

Objective To assess the role of sex as an independent prognostic factor for mortality in patients with sepsis admitted to intensive care units (ICUs). Design Systematic review and meta-analysis. Data sources MEDLINE, Embase, Web of Science, ClinicalTrials. gov and the WHO Clinical Trials Registry from inception to 17 July 2020. Study selection Studies evaluating independent associations between sex and mortality in critically ill adults with sepsis controlling for at least one of five core covariate domains prespecified following a literature search and consensus among experts. Data extraction and synthesis Two authors independently extracted and assessed the risk of bias using Quality In Prognosis Studies tool. Meta-analysis was performed by pooling adjusted estimates. The Grades of Recommendations, Assessment, Development and Evaluation approach was used to rate the certainty of evidence. Results From 14 304 records, 13 studies (80 520 participants) were included. Meta-analysis did not find sex-based differences in all-cause hospital mortality (OR 1.02, 95% CI 0.79 to 1.32; very low-certainty evidence) and all-cause ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low-certainty evidence). However, females presented higher 28-day all-cause mortality (OR 1.18, 95% CI 1.05 to 1.32; very low-certainty evidence) and lower 1-year all-cause mortality (OR 0.83, 95% CI 0.68 to 0.98; low-certainty evidence). There was a moderate risk of bias in the domain adjustment for other prognostic factors in six studies, and the certainty of evidence was further affected by inconsistency and imprecision. Conclusion The prognostic independent effect of sex on all-cause hospital mortality, 28-day all-cause mortality and all-cause ICU mortality for critically ill adults with sepsis was uncertain. Female sex may be associated with decreased 1-year all-cause mortality.post-print1281 K

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-7-methylguanosine (m(7)G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m(7)G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m(7)G tRNA methylation in cancer cell translation control and tumour biology

Sex as a prognostic factor for mortality in critically ill adults with sepsis: a systematic review and meta-analysis

Objective: To assess the role of sex as an independent prognostic factor for mortality in patients with sepsis admitted to intensive care units (ICUs). Design: Systematic review and meta- analysis. Data sources: MEDLINE, Embase, Web of Science, ClinicalTrials. gov and the WHO Clinical Trials Registry from inception to 17 July 2020. Study selection: Studies evaluating independent associations between sex and mortality in critically ill adults with sepsis controlling for at least one of five core covariate domains prespecified following a literature search and consensus among experts. Data extraction and synthesis: Two authors independently extracted and assessed the risk of bias using Quality In Prognosis Studies tool. Meta- analysis was performed by pooling adjusted estimates. The Grades of Recommendations, Assessment, Development and Evaluation approach was used to rate the certainty of evidence. Results: From 14 304 records, 13 studies (80 520 participants) were included. Meta- analysis did not find sex- based differences in all- cause hospital mortality (OR 1.02, 95% CI 0.79 to 1.32; very low- certainty evidence) and all- cause ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low- certainty evidence). However, females presented higher 28- day all- cause mortality (OR 1.18, 95% CI 1.05 to 1.32; very low- certainty evidence) and lower 1- year all- cause mortality (OR 0.83, 95% CI 0.68 to 0.98; low- certainty evidence). There was a moderate risk of bias in the domain adjustment for other prognostic factors in six studies, and the certainty of evidence was further affected by inconsistency and imprecision. Conclusion: The prognostic independent effect of sex on all- cause hospital mortality, 28- day all- cause mortality and all- cause ICU mortality for critically ill adults with sepsis was uncertain. Female sex may be associated with decreased 1- year all- cause mortality

Evaluation of the role of sex as a prognostic factor in critically ill adults with sepsis : systematic review protocol

Sepsis is a leading cause of mortality in critically ill patients. Recently, it has been recognised that sex may contribute to a differential risk for developing sepsis and it remains uncertain if the prognosis of sepsis varies between the sexes. The aim of this systematic review is to summarise the available evidence to assess the role of sex as a prognostic factor in patients with sepsis managed in the intensive care unit (ICU). This is a systematic review protocol of prognostic studies of sex in patients with sepsis managed in the ICU. The primary outcomes include all-cause hospital mortality and all-cause hospital mortality during the first 28 days. The secondary outcomes include all-cause hospital mortality during the first 7 days and all-cause mortality at 1 year. We will conduct a search strategy based on the population (sepsis), the prognostic factor (sex), the outcome of interest (mortality) and prognostic study methods. We will search in the following databases up to December 2019: MEDLINE Ovid (from 1976), Embase Elsevier (from 1974), Web of Science and two trial registries. We will impose no language restrictions. Two authors will independently screen titles, abstracts and full-text articles for eligibility of studies, and subsequently extract data. Two authors will independently assess the risk of bias of each study using the Quality in Prognostic Studies (QUIPS) tool. If possible, we will carry out a meta-analysis to provide a pooled prognostic effect estimate for each outcome. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence. Ethical approval will not be required. Findings from this review will be reported in a peer-reviewed scientific journal. Additionally, the results will be disseminated at conferences and in the mass media. CRD42019145054