Building Bivariate Tables: The compareGroups Package for R

The R package compareGroups provides functions meant to facilitate the construction of bivariate tables (descriptives of several variables for comparison between groups) and generates reports in several formats (LATEX, HTML or plain text CSV). Moreover, bivariate tables can be viewed directly on the R console in a nice format. A graphical user interface (GUI) has been implemented to build the bivariate tables more easily for those users who are not familiar with the R software. Some new functions and methods have been incorporated in the newest version of the compareGroups package (version 1.x) to deal with time-to-event variables, stratifying tables, merging several tables, and revising the statistical methods used. The GUI interface also has been improved, making it much easier and more intuitive to set the inputs for building the bivariate tables. The first version (version 0.x) and this version were presented at the 2010 useR! conference (Sanz, Subirana, and Vila 2010) and the 2011 useR! conference (Sanz, Subirana, and Vila 2011), respectively. Package compareGroups is available from the Comprehensive R Archive Network at http://CRAN.R-project.org/package=compareGroups

Métodos estadísticos para tratar incertidumbre en estudios de asociación genética: aplicación a CNVs y SNPs imputados

[spa] En los últimos años, se han descubierto un gran número de variantes genéticas de distinta naturaleza, desde las más simples que indican un cambio en un nucleótido (SNPs), hasta otras más complejas referentes al número de copias de un segmento de la cadena de ADN (CNVs). A pesar de que existen otras muchas variantes, como son las inversiones, microsatélites, etc., esta tesis se ha focalizado en los SNPs y en los CNVs, ya que son los dos tipos de variantes más analizadas en los estudios de epidemiología genética. En muchas situaciones, los métodos para analizar el efecto que tienen los SNPs o los CNVs sobre las enfermedades están bien resueltos. Sin embargo, en algunos casos, los SNPs y los CNVs se observan con incertidumbre. Por ejemplo, a veces el genotipo para un SNP no se observa directamente sino que se imputa. A su vez, establecer el número de copias para un CNV se hace de forma indirecta a partir de la señal cuantitativa de su sonda (probe). Esto hace que se requieran métodos estadísticos “no estándar” apropiados para estudiar la asociación entre SNPs imputados o CNVs incorporando esta incertidumbre. En la literatura se han descrito diferentes estrategias para afrontar los estudios de asociación entre una variante genética medida con incertidumbre y una variable respuesta: (i) la estrategia Naive y (ii) la estrategia conocida como Dosage. A grosso modo, la primera no tiene en cuenta la incertidumbre, mientras que la segunda lo hace de forma aproximada. En esta tesis doctoral se proponen y describen analíticamente modelos estadísticos para tratar datos genéticos medidos con incertidumbre que solventen las limitaciones que presentan los métodos existentes. Se demuestra que dichos modelos tienen la característica de incorporar la incertidumbre de forma adecuada en la función de verosimilitud. Además, se han escrito algoritmos numéricos para maximizar la función de verosimilitud de manera eficiente, a fin de poder analizar centenares de miles de variantes genéticas (estudios conocidos como GWAS –Genome Wide Association Studies-). El modelo propuesto es capaz de analizar distintos tipos de variable respuesta: binario (presencia o no de cierta enfermedad), cuantitativa (nivel de colesterol en sangre) ó censurada (tiempo hasta recaída). No sólo se han diseñado técnicas para el análisis de las variantes genéticas de forma individual sino también para pares simultáneamente (interacciones). Todo ello se ha implementado en distintas funciones estructuradas e integradas como parte de un programa de código libre y de uso común en la epidemiología genética como es R. Además, se ha escrito parte del código de las funciones en lenguaje C++ a fin de que los cálculos sean mucho más rápidos. El resultado ha sido la creación de un package de R llamado CNVassoc juntamente con un extenso manual de uso con numerosos ejemplos e instrucciones (vignette). Los artículos que conforman esta tesis son los siguientes: • “Accounting for uncertainty when assessing association between copy number and disease: a latent class model”, donde se presenta y describe el modelo propuesto. • “Genetic association analysis and meta-analysis of imputed SNPs in longitudinal studies”, donde se amplía el modelo al análisis de SNPs imputados en estudios con respuesta del tipo “tiempo hasta evento” (longitudinales). • “Interaction association analysis of imputed SNPs in case control and longitudinal studies”, donde se aplica el modelo a interacciones de pares de SNPs imputados en estudios de casos y controles y en estudios longitudinales. • “CNVassoc: Association analysis of CNV data using R”, en que se describe el package desarrollado e implementado en R junto con su vignette.[eng] In the last years, a large number of genetic variants have been discovered, from the simplest ones indicating a change in a nucleotide (SNPs), until the much more complex ones which are repetitions in a segment of DNA chain (CNVs). Although it exist more genetic variants such as microsatellites, inversions, etc. this thesis has focused on SNPs and CNVs, since these variants are the most analyzed by far. In many cases, the methods to analyze the effect of SNPs or CNVs on a disease are well solved. However, in some cases, SNPs and CNVs are measured with uncertainty. For example, sometimes the genotype for a SNP has not been directly observed but has been imputed instead. At the same time, to establish the number of copies for a CNV is done indirectly from the quantitative signal by a designed probe. This makes necessary “no standard” and appropriated statistical methods to study the association between imputed SNPs or CNVs incorporating this uncertainty. Several strategies have been described in the literature to perform association studies between a genetic variant measured with uncertainty and a response: (i) Naive strategy and (ii) a strategy known as Dosage. A grosso modo, the first does not take into account uncertainty, while the second does but in an approximated way. In this thesis, a statistical method is proposed to deal with genetic data measured with uncertainty and overcome the limitations of other existing methods. This method has been described analytically, which incorporates the uncertainty in the model likelihood properly. Also, numerical algorithms have been built to maximize the likelihood in an efficient way in order to analyze hundreds of thousand variants in a reasonable time (GWAS –Genome Wide Association Studies-). All this has been implemented in several functions structured and integrated as part of a free and very popular software in genetic epidemiology called R. Also, part of the code has been translated to C++ to speed up the process. Quantitative, binary or time-to-event response types are supported by the proposed method, covering the most popular designs in genetic association studies: case-control, quantitative traits or longitudinal studies. The method has been accommodated to perform interaction analysis (epistasis), as well

Standardized comparison of cardiovascular risk factors prevalence in spanish women and men living with hiv and in the general population

People living with HIV (PLWH) have an increased risk of cardiovascular (CV) disease, likely due to a higher prevalence of CV risk factors. We compared the age-standardized prevalence and management of CV risk factors in PLWH to that of the general population in Spain. Blood pressure, lipid, glucose, and anthropometric profiles were cross-sectionally compared along with the treatment of hypertension, dyslipidemia, and diabetes in a general population cohort and a PLWH cohort. Prevalence rates were standardized by the direct method by 10-year age groups in European standard populations and stratified by gender. We included 47,593 individuals aged 35 to 74 years, 28,360 from the general population cohort and 19,233 from the PLWH cohort. Compared to the general population, PLWH had a higher concentration of triglycerides (>35 mg/dL in women and >26 mg/dL in men) and a higher prevalence of smoking (>23% and >17%) and diabetes (>9.9% and >8.5%). The prevalence of treated diabetes, hypertension, and dyslipidemia were up to three-fold lower in both women and men living with HIV. There was a significant difference in PLWH compared to the general population in the lipid, glucose, and anthropometric profile. In addition, PLWH were less often treated for diagnosed diabetes, hypertension, and dyslipidemia

Multiple immunofluorescence assay identifies upregulation of Active beta-catenin in prostate cancer

Prostate cancer; Systems pathology; Wnt/β-catenin pathwayCàncer de pròstata; Patologia de sistemes; Via Wnt/β-cateninaCáncer de próstata; Patología de sistemas; Vía Wnt/β-cateninaOBJECTIVES: To apply a systems pathology-based approach to the quantification of nuclear Active β-catenin and human leukocyte antigen class I, and assess the biomarker involvement in a cohort of prostate tumor patients. RESULTS: The systems pathology approach applied allows a precise quantification of the marker expression in the different cell compartments as well as the determination of the areas that coexpress two markers. Our data shows that the accumulation of β-catenin in the nuclear compartment is significantly decreased in the adjacent normal areas when compared to tumor of the same patients (p < 0.001). In conclusion, the application of this novel multiple immunofluorescence assay demonstrates that the upregulation of Active β-catenin is a relatively common feature of prostate tumor development, and further supports the activation of the Wnt/β-catenin pathway in prostate cancer progression

Deformation and breakage of biofuel wood pellets

A convenient approach to employ an elliptic load-deformation elastoplastic approximation has been proposed and used to evaluate the mechanical behavior of pinewood biofuel pellets from lab-scale compressive load-deformation measurements. Verification of model predictions has been attempted against apparent finite element method based simulations. A database of essential mechanical properties has been established. This submission is intended as a model for being able to study the deformation and breakage behavior using lab-scale compression tests

DNA methylation biomarkers of myocardial infarction and cardiovascular disease

Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identifed biomarkers is still limited. We aimed to identify diferentially methylated loci associ‑ ated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers. Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infnium MethylationEPIC BeadChip. We performed a fxed efects meta-analysis of the two samples. 34 CpGs were associated with AMI. Only 12 of them were available in two independent cohort studies (n~1800 and n~2500) with incident coronary and cardiovascular disease (CHD and CVD, respectively). The Infnium HumanMethylation450 BeadChip was used in those two studies. Four of the 12 CpGs were validated in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. We then assessed whether methylation risk scores based on those CpGs improved the predictive capacity of the Framingham risk function, but they did not. Finally, we aimed to study the causality of those associations using a Mendelian randomization approach but only one of the CpGs had a genetic infuence and therefore the results were not conclusive. Conclusions: We have identifed 34 CpGs related to AMI. These loci highlight the relevance of smoking, lipid metab‑ olism, and infammation in the biological mechanisms related to AMI. Four were additionally associated with incident CHD and CVD but did not provide additional predictive informatio

Impact of a partial smoke-free legislation on myocardial infarction incidence, mortality and case-fatality in a population-based registry: the REGICOR Study

Abstract Background and Objective Coronary heart disease (CHD) is the leading cause of death, and smoking its strongest modifiable risk factor. Our aim was to determine the impact of the Spanish 2006 partial smoke-free legislation on acute myocardial infarction (AMI) incidence, hospitalization and mortality rates, and 28-day case-fatality in Girona, Spain. Methods Using a population-based registry (the REGICOR Study), we compared population incidence, hospitalization, and mortality rates, and 28-day case-fatality in the pre- and post-ban periods (2002-2005 and 2006-2008, respectively) by binomial regression analysis adjusted for confounding factors. We also analyzed the ban's impact on the outcomes of interest using the AMI definitions of the American Heart Association (AHA)/European Society of Cardiology (ESC) and the World Health Organization (WHO)-Monitoring trends and determinants in cardiovascular diseases (MONICA). Results In the post-ban period, AMI incidence and mortality rates significantly decreased (relative risk [RR] = 0.89; 95% confidence interval [CI] = 0.81-0.97 and RR = 0.82; 95% CI = 0.71-0.94, respectively). Incidence and mortality rates decreased in both sexes, especially in women, and in people aged 65-74 years. Former and non-smokers (passive smokers) showed diminished incidence rates. Implementation of the ban was not associated with AMI case-fatality. Models tended to be more significant with the WHO-MONICA than with the AHA/ESC definition. Conclusions The 2006 Spanish partial smoke-free legislation was associated with a decrease in population AMI incidence and mortality, particularly in women, in people aged 65-74 years, and in passive smokers. These results clarify the association between AMI mortality and the enactment of a partial smoke-free legislation and reinforce the effectiveness of smoking regulations in preventing CH

Increased COVID-19 mortality in people with previous cerebrovascular disease: a population-based cohort study

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Ictus hemorràgic; Ictus isquèmic; Hemorràgia subaracnoideaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Ictus hemorrágico; Ictus isquémico; Hemorragia subaracnoideaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemorrhagic stroke; Ischemic stroke; Subarachnoid hemorrhageBackground: The aim of the study was to determine the association between previous stroke and mortality after coronavirus disease 2019 (COVID-19) according to sex, age groups, and stroke subtypes. Methods: Prospective population-based cohort study including all COVID-19 positive cases between February 1 and July 31, 2020. Comorbidities and mortality were extracted using linked health administration databases. Previous stroke included transient ischemic attack, ischemic stroke, hemorrhagic stroke, spontaneous subarachnoid hemorrhage, and combined stroke for cases with more than one category. Other comorbidities were obesity, diabetes, hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cirrhosis, dementia, individual socioeconomic index, and deprivation index. Cases were followed up until December 31, 2020. Primary outcome was mortality of any cause after COVID-19 positivity. Cox proportional regression analysis adjusted for comorbidities was used. Stratified analyses were performed for sex and age (<60, 60-79, and ≥80 years). Results: There were 91 629 COVID-19 cases. Previous strokes were 5752 (6.27%), of which 3887 (67.57%) were ischemic, 1237 (21.50%) transient ischemic attack, 255 (4.43%) combined, 203 (3.53%) hemorrhagic, and 170 (2.96%) subarachnoid hemorrhage. There were 9512 deaths (10.38%). Mortality was associated with previous stroke (hazard ratio [HR]=1.12 [95% CI, 1.06-1.18]; P<0.001), in both sexes separately (men=1.13 [1.05-1.22]; P=0.001; women=1.09 [1.01-1.18]; P=0.023), in people <60 years (HR=2.97 [1.97-4.48]; P<0.001) and 60 to 79 years (HR=1.32 [1.19-1.48]; P<0.001) but not in people ≥80 years (HR=1.02 [0.96-1.09]; P=0.437). Ischemic (HR=1.11 [1.05-1.18]; P=0.001), hemorrhagic (HR=1.53 [1.20-1.96]; P=0.001) and combined (HR=1.31 [1.05-1.63]; P=0.016) strokes were associated but not transient ischemic attack. Subarachnoid hemorrhage was associated only in people <60 years (HR=5.73 [1.82-18.06]; P=0.003). Conclusions: Previous stroke was associated with a higher mortality in people younger than 80 years. The association occurred for both ischemic and hemorrhagic stroke but not for transient ischemic attack. These data might help healthcare authorities to establish prioritization strategies for COVID-19 vaccination.This work was supported, in part, by Spain’s Ministry of Health (Instituto de Salud Carlos III FEDER, RD16/0019/0002 and RD16/0019/0010 INVICTUS-PLUS