Extremely missing numerical data in Electronic Health Records for machine learning can be managed through simple imputation methods considering informative missingness: A comparative of solutions in a COVID-19 mortality case study.

BACKGROUND AND OBJECTIVE: Reusing Electronic Health Records (EHRs) for Machine Learning (ML) leads on many occasions to extremely incomplete and sparse tabular datasets, which can hinder the model development processes and limit their performance and generalization. In this study, we aimed to characterize the most effective data imputation techniques and ML models for dealing with highly missing numerical data in EHRs, in the case where only a very limited number of data are complete, as opposed to the usual case of having a reduced number of missing values. METHODS: We used a case study including full blood count laboratory data, demographic and survival data in the context of COVID-19 hospital admissions and evaluated 30 processing pipelines combining imputation methods with ML classifiers. The imputation methods included missing mask, translation and encoding, mean imputation, k-nearest neighbors' imputation, Bayesian ridge regression imputation and generative adversarial imputation networks. The classifiers included k-nearest neighbors, logistic regression, random forest, gradient boosting and deep multilayer perceptron. RESULTS: Our results suggest that in the presence of highly missing data, combining translation and encoding imputation-which considers informative missingness-with tree ensemble classifiers-random forest and gradient boosting-is a sensible choice when aiming to maximize performance, in terms of area under curve. CONCLUSIONS: Based on our findings, we recommend the consideration of this imputer-classifier configuration when constructing models in the presence of extremely incomplete numerical data in EHR.

Geographical and Temporal Variability of Ultra-Processed Food Consumption in the Spanish Population: Findings from the DRECE Study.

The consumption of ultra-processed foods (UPFs) has increased in recent decades, worldwide. Evidence on the negative impacts of food processing on health outcomes has also been steadily increasing. The aim of this study is to describe changes in consumption patterns of ultra-processed foods in the Spanish population over time and their geographical variability. Data from four representative cohorts of the Spanish population were used (1991−1996−2004−2008). Dietary information was collected using a validated frequency questionnaire and categorized using the NOVA classification. A total increase of 10.8% in UPF consumption between 1991 and 2008 was found in Spain (p-value < 0.001). The products contributing most to UPF consumption were sugar-sweetened beverages, processed meats, dairy products, and sweets. Those who consumed more ultra-processed foods were younger (p-value < 0.001) and female (p-value = 0.01). Significant differences between the different geographical areas of Spain were found. The eastern part of Spain was the area with the lowest UPF consumption, whereas the north-western part was the area with the highest increase in UPF consumption. Given the negative effect that the consumption of ultra-processed foods has on health, it is necessary to implement public health policies to curb this increase in UPF consumption.

Immunogenic dynamics and SARS-CoV-2 variant neutralisation of the heterologous ChAdOx1-S/BNT162b2 vaccination: Secondary analysis of the randomised CombiVacS study.

Background: The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180. Methods: Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739). Findings: In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49-5956·71) in the IG and 7298·22 BAU/mL (6739·41-7903·37) in the CG (p < 0·0001). RBD antibodies titres decreased at day 180 (1142·0 BAU/mL [1048·69-1243·62] and 1836·4 BAU/mL [1621·62-2079·62] in the IG and CG, respectively; p < 0·0001). Neutralising antibodies also waned from day 28 to day 180 in both the IG (1429·01 [1220·37-1673·33] and 198·72 [161·54-244·47], respectively) and the CG (1503·28 [1210·71-1866·54] and 295·57 [209·84-416·33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralising antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively). Interpretation: Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180. Funding: Funded by Instituto de Salud Carlos III (ISCIII).

The health status: the ignored risk factor in dementia incidence. NEDICES cohort.

BACKGROUND: The causes of the dementia decrease in affluent countries are not well known but health amelioration could probably play a major role. Nevertheless, although many vascular and systemic disorders in adult life are well-known risk factors (RF) for dementia and Alzheimer disease (AD), health status is rarely considered as a single RF. AIM: To analyse whether the health status and the self-perceived health (SPH) could be RF for dementia and AD and to discuss its biological basis. METHODS: We analysed different objective health measures and SPH as RF for dementia and AD incidence in 4569 participants of the NEDICES cohort by means of Cox-regression models. The mean follow-up period was 3.2 (range: 0.03-6.6) years. RESULTS: Ageing, low education, history of stroke, and "poor" SPH were the main RF for dementia and AD incidence, whereas physical activity was protective. "Poor" SPH had a hazard ratio = 1.66 (95% CI 1.17-2.46; p = 0.012) after controlling for different confounders. DISCUSSION: According to data from NEDICES cohort, SPH is a better predictor of dementia and AD than other more objective health status proxies. SPH should be considered a holistic and biologically rooted indicator of health status, which can predict future development of dementia and AD in older adults. CONCLUSIONS: Our data indicate that it is worthwhile to include the SPH status as a RF in the studies of dementia and AD incidence and to explore the effect of its improvement in the evolution of this incidence.

Two Dimensions of Nutritional Value: Nutri-Score and NOVA.

Front-of-pack labels can improve the ability of consumers to identify which foods are healthier, making them a useful public health tool. Nutri-Score is a front-of-pack labelling system adopted by several European countries. This system ranks foods according to their nutritional quality, but does not consider other dimensions such as the degree of food processing. The aim of this study is to compare the nutritional quality (as assessed by Nutri-Score) and the ultra-processing (as assessed by the NOVA classification) of foods in the Open Food Facts database. A simple correspondence analysis was carried out to study the relationship between the two systems. Ultra-processed foods (NOVA 4) were found in all Nutri-Score categories, ranging from 26.08% in nutritional category A, 51.48% in category B, 59.09% in category C, 67.39% in category D to up to 83.69% in nutritional category E. Given the negative effect that the consumption of ultra-processed foods has on different aspects of health, front-of-pack labelling with Nutri-Score should at least be accompanied by complementary labelling indicating the level of processing, such as the NOVA classification.

Ultra-processed food intake and all-cause mortality: DRECE cohort study.

OBJECTIVE: To determine the association between ultra-processed food (UPF) intake and all-cause mortality in a representative sample of Spanish population. DESIGN: Prospective cohort design in which follow-up lasted from baseline (1991) to mortality date or 31 December 2017, whichever was first. Dietary information was collected using a validated frequency questionnaire and categorised following the NOVA classification according to the extent of food processing. The association between consumption of UPF and mortality was analysed using Cox models. Isoenergetic substitution models were constructed to compare the health effects of the NOVA groups. SETTING: Cohort from the Diet and Risk of Cardiovascular Diseases (CVD) in Spain (DRECE) study, representative of the Spanish population. PARTICIPANTS: Totally, 4679 subjects between 5 and 59 years old. RESULTS: Average consumption of UPF was 370·8 g/d (24·4 % of energy intake). After a median follow-up of 27 years, 450 deaths occurred. Those who consumed the highest amount of UPF had higher risk of mortality. For every 10 % of the energy intake from UPF consumption, an increase of 15 % in the hazard of all-cause mortality was observed (HR 1·15; (95 % CI 1·03, 1·27); P-value = 0·012). Substitution of UPF with minimally processed foods was significantly associated with a decreased risk of mortality. CONCLUSIONS: An increase in UPF consumption was associated with higher risk of all-cause mortality in a representative sample of the Spanish population. Moreover, the theoretical substitution of UPF with unprocessed or minimally processed foods leads to a decrease in mortality. These results support the need to promote diets based on unprocessed or minimally processed foods.

Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). METHODS: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. FINDINGS: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. INTERPRETATION: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. FUNDING: Instituto de Salud Carlos III. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Performances of a Solution to Semi-Automatically Fill eCRF with Data from the Electronic Health Record: Protocol for a Prospective Individual Participant Data Meta-Analysis.

Clinical trial data collection still relies on a manual entry from information available in the medical record. This process introduces delay and error risk. Automating data transfer from Electronic Health Record (EHR) to Electronic Data Capture (EDC) system, under investigators' supervision, would gracefully solve these issues. The present paper describes the design of the evaluation of a technology allowing EHR to act as eSource for clinical trials. As part of the EHR2EDC project, for 6 ongoing clinical trials, running at 3 hospitals, a parallel semi-automated data collection using such technology will be conducted focusing on a limited scope of data (demographic data, local laboratory results, concomitant medication and vital signs). The evaluation protocol consists in an individual participant data prospective meta-analysis comparing regular clinical trial data collection to the semi-automated one. The main outcome is the proportion of data correctly entered. Data quality and associated workload for hospital staff will be compared as secondary outcomes. Results should be available in 2020.

Ivabradina para el control crónico de la frecuencia cardiaca en fibrilación auricular permanente. Diseño del proyecto BRAKE-AF / Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project

INTRODUCCIÓN Y OBJETIVOS: La ivabradina es un inhibidor de la corriente If, principal determinante de la función marcapasos del nódulo sinusal, aprobado como antianginoso y para tratar la insuficiencia cardiaca. Existen indicios sobre su capacidad para inhibir la conducción a través del nódulo auriculoventricular (NAV). Sobre esta base, el proyecto BRAKE-AF plantea el uso de ivabradina como agente cronotrópico negativo en fibrilación auricular (FA). MÉTODOS: Se realizará un ensayo clínico multicéntrico de fase III, aleatorizado, abierto, en paralelo, con diseño de no inferioridad, para comparar la ivabradina frente a la digoxina en 232 pacientes con FA permanente no controlada con bloqueadores beta o antagonistas del calcio; el objetivo primario es la reducción de la frecuencia cardiaca media diurna en un Holter de 24 h a los 3 meses. El ensayo se apoyará en un estudio electrofisiológico que analizará el efecto de la ivabradina en el potencial de acción del NAV humano, utilizando un modelo experimental en células de ovario de hámster chino transfectadas con el ADN que codifica la expresión de los distintos canales que componen dicho potencial de acción, registrando las corrientes iónicas mediante la técnica del parche de membrana. RESULTADOS: Se obtendrá información tanto del efecto de la ivabradina en las corrientes iónicas y el potencial de acción del NAV como de su eficacia y su seguridad en pacientes con FA permanente. CONCLUSIONES: Los resultados del proyecto BRAKE-AF podrían permitir que la ivabradina se incluyera en el limitado arsenal de fármacos disponibles actualmente para el control de frecuencia en la FA

INTRODUCTION AND OBJECTIVES: Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS: A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS: New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS: The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF

Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.

INTRODUCTION AND OBJECTIVES: Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS: A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS: New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS: The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT03718273.

The prognosis of patients hospitalized with a first episode of heart failure, validation of two scores: PREDICE and AHEAD.

PURPOSE: Heart failure (HF) is a chronic, frequent and disabling condition but with a modifiable course and a large potential for improving. The aim of this study was to validate the two available clinical prediction rules for mortality at one year in patients with primo-hospitalization for decompensated HF: PREDICE and AHEAD. The secondary aim was to evaluate in our setting the changes in the clinical pattern of HF in the last decade in patients hospitalized for a first episode of the disease. PATIENTS AND METHODS: A prospective multicenter cohort study, which included 180 patients hospitalized with "de novo" HF was conducted to validate the PREDICE score. Calibration and discrimination measurements were calculated for the PREDICE model and the PREDICE score (using the validation cohort of the PREDICE) and the AHEAD score (using both the development and the validation cohort of the PREDICE). RESULTS: For the PREDICE models, the area under the curve (AUC) was 0.68 (95% confidence interval [CI]: 0.57-0.79) and the calibration slope 0.65 (95% CI: 0.21-1.20). For the PREDICE score AUC was 0.59 (95% CI: 0.47-0.71) and slope 0.42 (95% CI: -0.20-1.17). For the AHEAD score the AUC was 0.68 (95% CI: 0.62-0.73) and slope 1.38 (95% CI: 0.62-0.73) when used the development cohort of PREDICE and the AUC was 0.58 (95% CI: 0.49-0.67), and slope 0.68 (95% CI: -0.06 to 1.47) when used its validation cohort. CONCLUSION: The present study shows that the two risk scores available for patients with primo-hospitalization for decompensated HF (PREDICE and AHEAD) are not currently valid for predicting mortality at one-year. In our setting the clinical spectrum of hospitalized patients with new-onset HF has been modified over time. The study underscores the need to validate the prognostic models before clinical implementation.

Cardiovascular Risk Factors Associated With Venous Thromboembolism.

Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures: A panel of several established cardiovascular risk factors. Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Evaluación de la validez de las funciones SCORE de bajo riesgo y calibrada para población española en las cohortes FRESCO / Validity assessment of low-risk SCORE function and SCORE function calibrated to the Spanish population in the FRESCO cohorts

Introducción y objetivos. Estudiar la validez de la función SCORE original de bajo riesgo sin y con colesterol unido a lipoproteínas de alta densidad y SCORE calibrada en población española. Métodos. Análisis agrupado con datos individuales de 12 estudios de cohorte de base poblacional. Se incluyó a 30.919 participantes de 40-64 años sin enfermedades cardiovasculares en el momento del reclutamiento, que se siguieron durante 10 años para la mortalidad cardiovascular contemplada en el proyecto SCORE. La validez de las funciones se analizó mediante el área bajo la curva ROC (discriminación) y el test de Hosmer-Lemeshow (calibración), respectivamente. Resultados. Se dispuso de 286.105 personas/año. La mortalidad a 10 años por causas cardiovasculares fue del 0,6%. La razón de casos esperados/observados fue de 9,1, 6,5 y 9,1 en varones y de 3,3, 1,3 y 1,9 en mujeres con las funciones SCORE original de bajo riesgo sin y con colesterol unido a lipoproteínas de alta densidad y SCORE calibrada, respectivamente; diferencias estadísticamente significativas con el test de calibración de Hosmer-Lemeshow entre la mortalidad predicha con SCORE y la observada (p < 0,001 en ambos sexos y en todas las funciones). Las áreas bajo la curva ROC con SCORE original fueron 0,68 en varones y 0,69 en mujeres. Conclusiones. Todas las versiones de las funciones SCORE disponibles en España sobreestiman significativamente la mortalidad cardiovascular observada en la población española. A pesar de la aceptable capacidad de discriminación, la predicción del número de acontecimientos cardiovasculares mortales (calibración) fue significativamente imprecisa (AU)

Introduction and objectives. To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. Methods. Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. Results. Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. Conclusions. All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate (AU)

Validity Assessment of Low-risk SCORE Function and SCORE Function Calibrated to the Spanish Population in the FRESCO Cohorts.

INTRODUCTION AND OBJECTIVES: To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. METHODS: Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. RESULTS: Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. CONCLUSIONS: All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate.

Variability of nutrients intake, lipid profile and cardiovascular mortality among geographical areas in Spain: The DRECE study.

It has often been suggested that cardiovascular mortality and their geographical heterogeneity are associated with nutrients intake patterns and also lipid profile. The large Spanish study Dieta y Riesgo de Enfermedades Cardiovasculares en España (DRECE) investigated this theory from 1991 to 2010. Out of the 4,783 Spanish individuals making up the DRECE cohort, 220 subjects (148 men and 72 women) died (4.62%) during the course of the study. The mean age of patients who died from cardiovascular causes (32 in all) was 61.08 years 95% CI (57.47-64.69) and 70.91% of them were males. The consumption of nutrients and the lipid profile by geographical area, studied by geospatial models, showed that the east and southern area of the country had the highest fat intake coupled to a high rate of unhealthy lipid profile. It was concluded that the spatial geographical analysis showed a relationship between high fat intake, unhealthy lipid profile and cardiovascular mortality in the different geographical areas, with a high variability within the country.

Improvement of serum lipids concentration in a general population historical cohort. Why? / Mejora de la concentración de lípidos séricos en una cohorte histórica de población general. ¿Por qué?

Background: Knowledge about the harmful effects of high levels of low-density lipoprotein cholesterol (cLDL) in adults increased after the publication of various guidelines, leading to closer control and more treatment. We hypothesized that these health care changes would result in an overall improvement in the lipid profile of the population. Objective: To determine the evolution of the lipid profile in the population of Spain from the Diet and Risk of Cardiovascular Disease in Spain cohort. Methods: A comparison was made between the baseline population-based probabilistically sampled DRECE cohort (DRECE 1 study, 1992-1994, n=4787) and its 13 years later revisit (DRECE 3 study, 2005-2007). A cross-sectional comparison was made of the overall population of DRECE1 and DRECE3, including only individuals aged 20 to 60 years (inter-individual variations). For subjects participating in both DRECE1 and DRECE3 (n=1039), individual variations over time (intra-individual analyses) were examined. Results: In the overall population, the prevalence of lipid-lowering therapy increased from 3.8% in DRECE1 to 10.7% in DRECE3. Comparing the lipid profile of the population aged 20-60 years in DRECE1 with the same age group in DRECE3, an overall decrease is observed in total cholesterol from a mean of 203.31mg/dl (SD 43.51) in 1992-1994 to 196.31mg/dl (SD 38.53) in 2005-2007, and in cLDL from a mean of 125.78mg/dl (SD 38.53) to 121.37mg/dl (SD 34.22). The proportion of the population with total cholesterol >200mg/dl decreased from 51% in DRECE1 to 47% in DRECE3, although this difference did not reach statistical significance (p=0.077). As regards the intra-individual analyses, total cholesterol increased from DRECE1 to DRECE3 in men and women younger than 40 years at baseline, but decreased in those who were older. Index of individuality for total cholesterol, cLDL, cHDL and triglycerides ranged from 0.53 to 0.87. Conclusions: The lipid profile of the Spanish population improved between 1992-1994 and 2005-2007. Within individuals, lipid concentrations, especially total cholesterol and cLDL have increased, although the trend is favorable in the middle-age group (40-59 years). These changes seem to be due to several causes, impacted by dietary and lifestyle factors, and also by a greater emphasis in lipid-lowering therapy in middle-aged people. Lipid parameters had a low index of individuality, which limits their usefulness as population reference values (AU)

Antecedentes: Los efectos nocivos de los altos niveles de colesterol ligado a lipoproteínas de baja densidad (cLDL) han sido ampliamente difundidos en la literatura científica y popular. Nuestra hipótesis es que estas recomendaciones han influido eficazmente en el perfil lípido de la población española. Objetivo: Determinar la evolución del perfil de lípidos en la población de España a partir de la cohorte Dieta y riesgo de enfermedad cardiovascular en España (DRECE). Métodos: Se comparó la cohorte de partida DRECE (estudio DRECE1, 1992-1994, n=4.787), procedente de muestreo probabilístico poblacional, con su reevaluación a los 13 años (estudio DRECE3, 2005-2007). Se compararon de modo transversal las muestras DRECE1 y DRECE3, incluyendo solo sujetos entre 20 y 60 años (variaciones interindividuales). De los sujetos que participaron en ambos estudios (n=1.039) se examinaron las variaciones interindividuales a lo largo del tiempo (análisis intraindividual). Resultados: En la población general, la prevalencia de la terapia hipolipidemiante aumentó de 3,8% en DRECE1 a 10,7% en DRECE3. Al comparar el perfil lipídico de la población de 20 a 60 años en DRECE1 con el mismo grupo de edad en DRECE3 disminuye la media del colesterol total de 203,31mg/dl (DS 43,51) en 1992-1994 a 196,31mg/dl (DS 38,53) en 2005-2007, la media del cLDL disminuye de 125,78mg/dl (DS 38,53) a 121,37mg/dl (DS 34,22). La proporción de la población con colesterol total>200mg/dl se redujo de 51% en DRECE1 al 47% en DRECE3, aunque esta diferencia no fue significativa (p=0,077). Respecto del análisis intraindividual el colesterol total aumentó de DRECE1 a DRECE3 en hombres y mujeres menores de 40 años al inicio de la cohorte, y descendió en los mayores de 40. El índice de individualidad del colesterol total, cLDL, cHDL y triglicéridos osciló entre 0,53 y 0,87. Conclusiones: El perfil lipídico de la población española mejoró entre 1992-1994 y 2005-2007. La concentración intraindividual de lípidos aumentó ligeramente, especialmente el colesterol total y cLDL, pero la tendencia fue más favorable en los sujetos de edad media (40-59 años). Estos cambios parecen ser multicausales, influidos por factores dietéticos y de estilo de vida, y también por un mayor énfasis en la terapia hipolipidemiante en sujetos en edad media. Los parámetros lipídicos tenían un bajo índice de individualidad, lo que limita su utilidad como valores de referencia poblacionales (AU)

Improvement of serum lipids concentration in a general population historical cohort. Why?

BACKGROUND: Knowledge about the harmful effects of high levels of low-density lipoprotein cholesterol (cLDL) in adults increased after the publication of various guidelines, leading to closer control and more treatment. We hypothesized that these health care changes would result in an overall improvement in the lipid profile of the population. OBJECTIVE: To determine the evolution of the lipid profile in the population of Spain from the Diet and Risk of Cardiovascular Disease in Spain cohort. METHODS: A comparison was made between the baseline population-based probabilistically sampled DRECE cohort (DRECE 1 study, 1992-1994, n=4787) and its 13 years later revisit (DRECE 3 study, 2005-2007). A cross-sectional comparison was made of the overall population of DRECE1 and DRECE3, including only individuals aged 20 to 60 years (inter-individual variations). For subjects participating in both DRECE1 and DRECE3 (n=1039), individual variations over time (intra-individual analyses) were examined. RESULTS: In the overall population, the prevalence of lipid-lowering therapy increased from 3.8% in DRECE1 to 10.7% in DRECE3. Comparing the lipid profile of the population aged 20-60 years in DRECE1 with the same age group in DRECE3, an overall decrease is observed in total cholesterol from a mean of 203.31mg/dl (SD 43.51) in 1992-1994 to 196.31mg/dl (SD 38.53) in 2005-2007, and in cLDL from a mean of 125.78mg/dl (SD 38.53) to 121.37mg/dl (SD 34.22). The proportion of the population with total cholesterol >200mg/dl decreased from 51% in DRECE1 to 47% in DRECE3, although this difference did not reach statistical significance (p=0.077). As regards the intra-individual analyses, total cholesterol increased from DRECE1 to DRECE3 in men and women younger than 40 years at baseline, but decreased in those who were older. Index of individuality for total cholesterol, cLDL, cHDL and triglycerides ranged from 0.53 to 0.87. CONCLUSIONS: The lipid profile of the Spanish population improved between 1992-1994 and 2005-2007. Within individuals, lipid concentrations, especially total cholesterol and cLDL have increased, although the trend is favorable in the middle-age group (40-59 years). These changes seem to be due to several causes, impacted by dietary and lifestyle factors, and also by a greater emphasis in lipid-lowering therapy in middle-aged people. Lipid parameters had a low index of individuality, which limits their usefulness as population reference values.

Prognostic models for locally advanced cervical cancer: external validation of the published models.

OBJECTIVE: To externally validate the prognostic models for predicting the time-dependent outcome in patients with locally advanced cervical cancer (LACC) who were treated with concurrent chemoradiotherapy in an independent cohort. METHODS: A historical cohort of 297 women with LACC who were treated with radical concurrent chemoradiotherapy from 1999 to 2014 at the 12 de Octubre University Hospital (H12O), Madrid, Spain. The external validity of prognostic models was quantified regarding discrimination, calibration, measures of overall performance, and decision curve analyses. RESULTS: The review identified 8 studies containing 13 prognostic models. Different (International Federation of Gynecology and Obstetrics [FIGO] stages, parametrium involvement, hydronephrosis, location of positive nodes, and race) but related cohorts with validation cohort (5-year overall survival [OS]=70%; 5-year disease-free survival [DFS]=64%; average age of 50; and over 79% squamous cell) were evaluated. The following models exhibited good external validity in terms of discrimination and calibration but limited clinical utility: the OS model at 3 year from Kidd et al.'s study (area under the receiver operating characteristic curve [AUROC]=0.69; threshold of clinical utility [TCU] between 36% and 50%), the models of DFS at 1 year from Kidd et al.'s study (AUROC=0.64; TCU between 24% and 32%) and 2 years from Rose et al.'s study (AUROC=0.70; TCU between 19% and 58%) and the distant recurrence model at 5 years from Kang et al.'s study (AUROC=0.67; TCU between 12% and 36%). CONCLUSION: The external validation revealed the statistical and clinical usefulness of 4 prognostic models published in the literature.

Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis.

OBJECTIVE: Diabetes is a common cause of shortened life expectancy. We aimed to assess the association between diabetes and cause-specific death. RESEARCH DESIGN AND METHODS: We used the pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79 years old. Diabetes status was self-reported or defined as glycemia >125 mg/dL at baseline. Vital status and causes of death were ascertained by medical records review and linkage with the official death registry. The hazard ratios and cumulative mortality function were assessed with two approaches, with and without competing risks: proportional subdistribution hazard (PSH) and cause-specific hazard (CSH), respectively. Multivariate analyses were fitted for cardiovascular, cancer, and noncardiovascular noncancer deaths. RESULTS: We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63-2.52) and PSH = 1.99 (1.60-2.49) in men; and CSH = 2.28 (1.75-2.97) and PSH = 2.23 (1.70-2.91) in women; 2) cancer death, CSH = 1.37 (1.13-1.67) and PSH = 1.35 (1.10-1.65) in men; and CSH = 1.68 (1.29-2.20) and PSH = 1.66 (1.25-2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23-1.91) and PSH = 1.50 (1.20-1.89) in men; and CSH = 1.89 (1.43-2.48) and PSH = 1.84 (1.39-2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes. CONCLUSIONS: Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes. The use of CSH and PSH provides a comprehensive view of mortality dynamics in a population with diabetes.