Carla Henriques

Estimation of a two-dimensional distribution function under association

Abstract By considering an associated and strictly stationary sequence of random variables, say X n , n⩾1 , we study the properties of an histogram estimator for the two-dimensional distribution function of (X1,Xk+1). We find conditions on the covariance structure of the original random variables for the almost sure convergence of the estimator and for the convergence in distribution of the finite dimensional distributions. We also characterize the mean square error (MSE) and find its convergence rate, under assumptions on the convergence rate of the covariances.

Combined C4d and CD3 immunostaining predicts immunoglobulin (Ig)A nephropathy progression

A number of molecules have been shown recently to be involved in the pathogenesis and progression of immunoglobulin (Ig)A nephropathy (IgAN). Among these, we have selected C4d (complement lectin pathway involvement), CD3 (T cell marker, traducing interstitial inflammation), transglutaminase 2 (TGase‐2, involved in tissue fibrosis development) and p‐extracelluar‐regulated kinase (ERK)1/2 (protein kinase intracellular signaling molecule) to perform a panel of immunohistological biomarkers and assess its predictive value for disease progression. Immunohistochemical staining of these biomarkers was performed in paraffin sections from 74 renal biopsy cases with the clinical diagnosis of IgAN. Association between score analysis of these parameters and disease course was assessed through univariate and multivariate analysis, including baseline clinical and histological data. Univariate analysis showed that glomerular C4d, tubulointerstitial TGase2 and CD3 scores were associated with baseline proteinuria and disease progression. Multivariate analysis showed that only baseline estimated glomerular filtration rate (eGFR), C4d and CD3 were associated independently with progressive kidney disease (decline of at least 50% in the eGFR or progression to end‐stage renal disease (ESRD) during the follow‐up period). Establishing an accurate prediction model for IgAN progression is still a matter of research in clinical nephrology. The complement system, particularly lectin pathway activation, and T cell activation, have been shown previously to be potential modifiers of the disease course. Here we show that the combination of two histological biomarkers (C4d and CD3) can be a powerful predictor of IgAN progression and a potential useful tool for the clinical approach of this disease.

Criteria to predict carriers of a novel SCN5A mutation in a large Portuguese family affected by the Brugada syndrome

AIMS Brugada syndrome (BrS) is a life-threatening arrhythmia disorder associated with autosomal-dominant mutations in the SCN5A gene. We aimed to characterize the diagnostic challenges and clinical manifestations of a novel SCN5A mutation associated with BrS. METHODS AND RESULTS From a novel SCN5A mutation (c.664C>T; p.Arg222X) identified in a proband with the characteristic electrocardiographic pattern and the history of sudden collapse, 122 family members were studied including 40 carriers of the mutation. The electrocardiographic diagnosis of BrS requires type 1 Brugada electrocardiogram (ECG) pattern in >1 right precordial lead (V1-V3), but recently an isolated lead with coved-type ECG was proposed to be enough for the diagnosis. In this family, these proposed criteria (PC) were more sensitive in detecting mutation carriers than the conventional criteria without repercussion on the specificity. Carriers had, on average, longer P-wave duration, PR, and QRS intervals and higher transmural dispersion of repolarization. The prevalence of late potentials was higher in carriers, and individual signal average ECG (SAECG) parameters (QRSf, LAS, and RMS40) also were related to SCN5A gene mutation. Three non-carriers were found to be affected by BrS, two with a spontaneous type 1 ECG with alternative placement of the precordial electrodes, and one only after the pharmacological provocative test, suggesting that other genes may play a role in the pathophysiology of this disease. CONCLUSION The PC for BrS diagnosis should be implemented. Some parameters from the spontaneous ECG and the SAECG are more effective tools than the characteristic repolarization pattern to discriminate between carriers of SCN5A mutations.

Recent Developments in Modeling and Applications in Statistics

Sampling and Modeling.- Estimation.- Extremes.- Testing Statistical Hypothesis.- Models with Stochastic Differential Equations.- Stochastic Processes.

Convergence rates for the estimation of two-dimensional distribution functions under association and estimation of the covariance of the limit empirical process

Let X n , n≥1, be an associated and strictly stationary sequence of random variables, having marginal distribution function F. The limit in distribution of the empirical process, when it exists, is a centred Gaussian process with covariance function depending on terms of the form ϕ k (s, t)=P(X 1 s, X k+1 t)−F(s)F(t). We prove the almost sure consistency for the histogram to estimate each ϕ k and also to estimate the covariance function of the limit empirical process, identifying, for both, uniform almost sure convergence rates. The convergence rates depend on a suitable version of an exponential inequality. The rates obtained, assuming the covariances to decrease geometrically, are of order n −1/3log2/3 n for the estimator of ϕ k and of order n −1/3log5/3 n for the estimator of the covariance function.

Brugada Syndrome Diagnosis: Three Approaches to Combining Diagnostic Markers

Brugada syndrome (BS) is an inherited cardiopathy that predisposes individuals without structural heart disease to sudden cardiac death. The diagnosis is performed by detecting a typical pattern in the electrocardiogram (ECG), called Type 1 Brugada pattern, but this is not always visible, so the diagnosis is not straightforward. In this study, we investigated other ECG markers, independent of the typical pattern, which exhibited a good ability to differentiate the carriers and the non-carriers of the genetic mutation responsible for this disease. The combination of these markers through linear models has led to enhancing the ability of each marker to discriminate between the two groups. We found linear combinations of these markers for which the area under the ROC curve (AUC) was greater than 0.9, which suggests an excellent ability to discriminate between the two groups. This study points towards good alternatives for diagnosing BS which may prevent searching for the Type 1 Brugada pattern in an ECG, but these alternatives should be investigated with a larger database in order to produce a good effective predictive model.

Study of the Electrocardiographic Fluctuations on Brugada Syndrome Screening

Brugada syndrome (BS) is a cardiologic disorder which favours cardiac arrhythmias and is thought to be responsible for about 20–50 % of sudden cardiac death (SCD) in individuals with a structurally normal heart. There are three electrocardiogram (ECG) characteristic patterns associated with BS. From an index case, 130 family members were screened for BS and data collected in order to identify possible influential factors for the manifestation, and fluctuations, of Brugada patterns in ECG results. Moreover, data collected from family members were analysed in order to evaluate the necessity for more than one ECG in screening for BS. Also, the effect of displacing ECG electrodes in the sensitivity and specificity of the exam was analysed.

Positioning of the egc leads in Brugada Syndrome: higher sensitivy with lower specificity? Answers from a genetically characterized family

Monday, October 5, 2009