Browsing by Author "Medeiros, Ana Margarida"
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- Adult cascade screening versus child reverse cascade screening in Familial HypercholesterolemiaPublication . Miranda, Beatriz Raposo; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, Mafalda; on behalf of the Portuguese FH Study investigatorsFamilial hypercholesterolemia (FH) is a common inherited lipid disorder that predisposes to cardiovascular disease (CVD). Despite most cascade screening programs are initiated by adult index cases, reverse cascade screening pediatric index cases is starting to be described. Therefore, we aimed to assess the outcome of adult cascade screening and child reverse cascade screening strategies in families from the Portuguese FH Study (PFHS). The PFHS database was consulted, and 423 index cases genetically identified with FH (224 adults and 199 children) and their 997 relatives referred to the PFHS were analysed. From 224 adults with FH, 485 relatives were enrolled for cascade screening and 290 were identified with FH. From 199 paediatric cases with FH, 512 relatives were screened and 286 were identified with FH. Child reverse cascade screening presented a slightly higher diagnostic rate than adult cascade screening, 1.44 vs 1.29 new cases with FH per index case, and the age of the relatives identified was younger, 29 vs 37 years. For 94% of index children, relatives were referred (2.56 relatives per index), in contrast with the adult cohort whereas only 70% were referred with family-members (2.17 relatives per index). Overall, both screening approaches constitute valuable tools to identify new cases with FH, but the child reverse cascade screening creates the opportunity for more relatives to be tested at a younger age. It is crucial to improve relatives' recruitment rate since early identification allows a correct FH diagnosis and treatment to prevent CVD.
- Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers for the correct assessment of monogenic dyslipidemiaPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Aguiar, Pedro; Bourbon, Mafalda
- Cascade Screening in Familial Hypercholesterolemia: Adult cascade screening versus CHILD reverse cascade screeningPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is an inherited lipid disorder that increases the risk of developing cardiovascular disease (CVD). Despite most cascade screening programs are initiated by adult index cases, reverse cascade screening pediatric index cases is starting to be described. Therefore, in this work, we aimed to assess the outcome of both creening strategies (adult cascade screening and child reverse cascade screening) in families from the Portuguese FH Study (PFHS). The PFHS database was consulted, and 423 index cases genetically identified with FH (224 adults and 199 children) and their 997 relatives referred to the PFHS were analysed. From 224 adults with FH, 485 relatives were enrolled for cascade screening and 290 were identified with FH. From 199 paediatric cases with FH, 512 relatives were screened and 286 were identified with FH. Child reverse cascade screening presented a slightly higher diagnostic rate than adult cascade screening, 1.44 vs 1.29 new cases with FH per index case, and the age of the relatives identified was younger, 29 vs 37 years. For 94% of index children, relatives were referred (2.56 relatives per index), in contrast with the adult cohort whereas only 70% were referred with family-members (2.17 relatives per index). Overall, both screening approaches constitute valuable tools to identify new cases with FH, but the child reverse cascade screening notably creates the opportunity for more relatives to be tested at a younger age. However, it remains crucial to improve relatives' recruitment rate since early identification allows a correct FH diagnosis and treatment to prevent CVD.
- Characterization of the First PCSK9 Gain of Function HomozygotePublication . Alves, Ana Catarina; Etxebarria, Aitor; Medeiros, Ana Margarida; Benito-Vicente, Asier; Thedrez, Aurélie; Passard, Maxime; Croyal, Mikaël; Martin, Cesar; Lambert, Gilles; Bourbon, MafaldaGain of function (GOF) mutations in proprotein convertase subtilisin kexin type 9 (PCSK9) are a rare cause of familial hypercholesterolemia (FH). We identified a child with a clinical diagnosis of FH with 2 novel putative PCSK9 GOF missense variants (p.[(Ala62Asp)]; [(Pro467Ala)]), and no mutation in the low-density lipoprotein (LDL) receptor (LDLR) or in apolipoprotein B100 (APOB) genes. The proband was referred to the Portuguese FH Study (1) at age 11 and presented a total cholesterol of 316 mg/dl and low-density lipoprotein cholesterol (LDL-C) of 234 mg/dl on a strict diet. The phenotype presented by all PCSK9 heterozygous carriers within this large pedigree is similar to APOB heterozygous carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 211.57 ± 42.02 mg/dl; p = 0.227) but significantly different than heterozygous LDLR carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 230.63 ± 76.50 mg/dl; p = 0.012) when comparing the relatives’ phenotype in our cohort.
- Classification Methods Applied to Familial Hypercholesterolemia Diagnosis at Pediatric Age: Comparison of Simon Broome Criteria with Modified Decision Tree ModelsPublication . Albuquerque, João; Medeiros, Ana Margarida; Alves, Ana Catarina; Antunes, Marília; Bourbon, MafaldaIntroduction: Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, resulting in severe dyslipidemia and increased CVD risk. Simon Broome (SB) criteria for the diagnostic of FH are among the most frequently used in clinical setting, and are based on elevated total cholesterol (TC) and low density lipoprotein (LDLc) cholesterol levels, presence of tendinous xanthomas and family history [1]. The molecular diagnosis that confirms this diagnosis reveals, however, a high false positive rate when following these criteria, which can represent a heavy burden in terms of healthcare costs. The main purpose of this work was to develop alternative classification models for FH diagnosis, based on different decision tree (DT) algorithms, using commonly available biochemical markers as predictors.
- Classification methods applied to the diagnosis of pediatric patients with familial hypercholesterolemia: comparison of Simon Broome criteria with logistic regression and modified decision tree modelsPublication . Albuquerque, João; Antunes, Marília; Alves, Ana Catarina; Medeiros, Ana Margarida; Bourbon, MafaldaFamilial Hypercholesterolemia (FH) is a monogenic disorder of lipid metabolism, resulting in severe dyslipidemia and increased cardiovascular disease risk. Simon Broome (SB) criteria for the diagnostic of FH are among the most frequently used in clinical setting, and are based on elevated total cholesterol (TC) and low density lipoprotein (LDLc) cholesterol levels, presence of tendinous xanthomas and family history, although only genetic testing can confirm the diagnosis. According to the Portuguese Study of Familial Hypercholesterolemia (EPHF), only around 42% of the patients with clinical criteria reveal a positive diagnostic for FH, a high false positive rate that represents a heavy burden in terms of healthcare costs. The main purpose of this work was to develop alternative classification models for FH diagnosis based on two different methods, logistic regression (LR) and decision trees (DT), using several biochemical indicators as predictor variables. Both models were compared with SB clinical criteria in terms of accuracy and efficiency, through bootstrap resampling techniques.
- Comparative study between a Logistic Regression Model and Simon Broome Criteria for the Diagnosis of Pediatric Patients with Familial HypercholesterolemiaPublication . Albuquerque, João; Alves, Ana Catarina; Medeiros, Ana Margarida; Bourbon, Mafalda; Antunes, MaríliaIntroduction: Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, resulting in severe dyslipidemia and increased cardiovascular disease risk. Simon Broome (SB) criteria for the diagnostic of FH are among the most frequently used in clinical setting, and are based on elevated total cholesterol (TC) and low density lipoprotein cholesterol (LDLc) levels, presence of tendinous xanthomas and family history, although only genetic testing can confirm the diagnosis [1]. According to the Portuguese FH Study, only around 42% of the patients with clinical criteria reveal a positive diagnostic for FH [2], a high false positive rate that represents a heavy burden in terms of healthcare costs. The main purpose of this work was to develop an alternative classification method for FH diagnosis based on a logistic regression (LR) model, using several biochemical indicators as predictor variables. For this purpose, different operating characteristics (OC) were compared between both models, through bootstrap resampling techniques.
- Comparative study on the performance of different classification algorithms, combined with pre- and post-processing techniques to handle imbalanced data, in the diagnosis of adult patients with familial hypercholesterolemiaPublication . Albuquerque, João; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, Mafalda; Antunes, MaríliaFamilial Hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism. Current criteria for FH diagnosis, like Simon Broome (SB) criteria, lead to high false positive rates. The aim of this work was to explore alternative classification procedures for FH diagnosis, based on different biological and biochemical indicators. For this purpose, logistic regression (LR), naive Bayes classifier (NB), random forest (RF) and extreme gradient boosting (XGB) algorithms were combined with Synthetic Minority Oversampling Technique (SMOTE), or threshold adjustment by maximizing Youden index (YI), and compared. Data was tested through a 10 x 10 repeated k-fold cross validation design. The LR model presented an overall better performance, as assessed by the areas under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves, and several operating characteristics (OC), regardless of the strategy to cope with class imbalance. When adopting either data processing technique, significantly higher accuracy (Acc), G-mean and F-1 score values were found for all classification algorithms, compared to SB criteria (p < 0.01), revealing a more balanced predictive ability for both classes, and higher effectiveness in classifying FH patients. Adjustment of the cut-off values through pre or post-processing methods revealed a considerable gain in sensitivity (Sens) values (p < 0.01). Although the performance of pre and post-processing strategies was similar, SMOTE does not cause model's parameters to loose interpretability. These results suggest a LR model combined with SMOTE can be an optimal approach to be used as a widespread screening tool.
- Dislipidemia e risco cardiovascular em crianças: identificação de biomarcadores para uma melhor diferenciação entre uma dislipidemia monogénica e uma dislipidemia poligénica/externaPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Aguiar, Pedro; Bourbon, Mafalda
- Estudo Português de Hipercolesterolemia FamiliarPublication . Medeiros, Ana MargaridaA hipercolesterolemia familiar é uma das dislipidemias genéticas mais comuns, caracterizada por valores elevados de LDL, xantomas tendinosos e desenvolvimento precoce de aterosclerose e doença coronária prematura. É uma patologia autossómica, monogénica, dominante, cujo diagnóstico precoce é essencial para aumentar a esperança média de vida dos doentes, bem como para identificação dos seus familiares em risco.